Aldafermin (NGM282) for Chronic Diarrhea Due to Bile Acid Malabsorption (BAM)

Study Overview
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Brief Summary
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This single-center, randomized, double-blind, placebo-controlled study is designed to compare effects of aldafermin, (NGM282), 1 mg, and placebo given daily by subcutaneous injection on bowel functions and hepatic synthesis and fecal excretion of bile acids in patients with diarrhea associated with bile acid malabsorption (BAM).

Detailed Description
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This single-center, randomized, double-blind, placebo-controlled study is designed to compare effects of aldafermin, NGM282, 1 mg, and placebo given daily by subcutaneous injection on bowel functions and hepatic synthesis and fecal excretion of bile acids in patients with diarrhea associated with bile acid malabsorption (BAM). Thirty patients will receive either aldafermin (NGM282) or placebo, not both. The study includes a 7 to 28-day long prescreen period and a 28-day long treatment period for a maximum study duration of 56 days. Bowel pattern will be assessed by patient-recorded daily bowel pattern diaries. Serum 7-alpha C4 (C4) and fibroblast growth factor 19 (FGF-19) and fecal bile acids will be measured at baseline and Day 14 and Day 28 of treatment. Safety will be assessed through regular monitoring of adverse events, clinical laboratory results, 12-lead ECGs, physical examinations, and vital signs.

Official Title
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A Randomized, Double-Blind, Placebo Controlled Trial of Aldafermin (NGM282) for Treatment of Chronic Diarrhea Due to Bile Acid Malabsorption (BAM)

Conditions
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Chronic Diarrhea, Irritable Bowel Syndrome With Diarrhea, Bile Acid Malabsorption, Bile Acid Diarrhea, Bile Acid Malabsorption Syndrome Type II, Functional Diarrhea

Intervention / Treatment
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* Drug: Aldafermin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged 18 to 75 years, inclusive at Visit 1 Screen. Clinical diagnosis of functional diarrhea or IBS with diarrhea according to Rome III or IV criteria at Visit 1 Screen. Clinical laboratory evidence of BAM (20-22), with at least one of the following results recorded in their past medical history: Serum C4 ≥ 52 ng/mL Fecal BA > 2337 µmoles / 48 hours Total fecal BA > 1000 µmoles / 48 hours + 4 % primary BA Fecal primary BA > 10% / 48 hours Body mass index (BMI) 18.0 to 45.0 kg/m2, inclusive at Visit 1 Screen Understands the study procedures, is willing and able to comply with the study procedures, and is able to give informed consent If treated with any of the following medications, dosing must be stable for 30 days prior to Visit 1 Screen. Patient must agree to maintain the same dose of medication throughout the study: Tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs). Bile acid sequestrants such as colestipol, cholestyramine and colesevelam. Participants must use one highly effective method of contraception for 30 days before the study through 90 days after study completion for males and through 30 days after study completion for females. Highly effective methods of contraception include: Oral, implantable, transdermal or injectable hormonal contraceptives; standard intrauterine device or vaginal ring; Male or female condoms and diaphragms used with spermicide; abstinence from heterosexual intercourse; female partners exclusively sexually active with a surgically sterilized male partner. Females who are surgically sterile having experienced a prior hysterectomy, bilateral salpingectomy, or bilateral oophorectomy or postmenopausal (defined as12 consecutive months with no menses) are not considered to be of childbearing potential. Exclusion Criteria: Pregnant or lactating Structural or metabolic diseases/conditions that affect the gastrointestinal system Use of the following medications at least 14 days prior to Visit 1 throughout the duration of the treatment period Patients may elect to withdraw from bile acid sequestrants such as colestipol, cholestyramine and colesevelam or they may continue but they must continue at the same dose throughout the study. GI medications including: Anti-nausea agents including trimethobenzamide, promethazine, prochlorperazine, dimenhydrinate, hydroxyzine Osmotic laxative agents including lactulose, sorbitol or PEG solutions as Miralax and Glycolax Prokinetic agents including tegaserod, metoclopramide, prucalopride, domperidone, erythromycin, clarithromycin and azithromycin. 5-HT3 antagonists including alosetron, ondansetron, tropisetron Drugs with a known pharmacological activity at 5-HT4, 5-HT2b or 5-HT3 receptors including tegaserod, ondansetron, granisetron and tropisetron All narcotics including codeine, morphine, and propoxyphene, either alone or in combination Anti-cholinergics including dicyclomine, hyoscyamine, propantheline. Antimuscarinics Tramadol Peppermint oil Systemic antibiotics and antibiotics directed at colonic flora including rifaximin and metronidazole Use of CNS stimulant medications, including methylphenidate, atomoxetine, modafinil, amphetamines or phentermine. Clinically relevant changes in dietary, lifestyle, or exercise regimen within 30 days prior to Visit 1 Screen and throughout the duration of the study Any colonic or major abdominal surgery including bariatric surgery, gastric banding, stomach surgery and intestinal or colonic surgery. Procedures such as appendectomy, cholecystectomy, hysterectomy, caesarean section, or polypectomy are allowed as long as they have occurred at least 3 months prior to Visit 1 Screen. .History of colorectal cancer, inflammatory bowel disease, diverticulitis, ischemic colitis, microscopic colitis or celiac disease History of organic abnormalities of the GI tract, intestinal obstruction, stricture, toxic megacolon, GI perforation, or impaired intestinal circulation. Other GI diseases such as GI bleeding or ulcerations History of cerebrovascular disease including stroke, TIA, acute coronary syndrome, myocardial infarction or unstable angina Clinically significant cardiac history or presence of electrocardiogram (ECG) findings at Visit 1 Screen: Abnormal heart rate < 40 or > 100 beats per minute QTc interval > 470 milliseconds (ms) QRS interval ≥ 110 ms PR interval ≥ 220 ms Hepatic dysfunction including abnormal serum alanine aminotransferase [ALT] or aspartate transaminase [AST] > 3 × upper limit of normal [ULN]); total direct bilirubin > 2 × ULN, or alkaline phosphatase > 2 × ULN at Visit 1 Screen Clinically significant renal insufficiency including serum creatinine > 2.5 mg/dL at Visit 1 Screen History of severe head injury or history of seizures History of suicide attempt or a hospitalization for a major psychiatric condition within 1 year prior to Visit 1 Screen. At Visit 1 Screen or during the optional remote consent and eligibility review, participants will complete the Hospital Anxiety and Depression questionnaire. If either score for anxiety or depression individually exceeds 8, the score will be discussed. The patient will be and advised whether to participate or whether to see their primary care physician. History of alcohol use disorder or substance use disorder within 2 years of Visit 1 Screen. Significant history or clinical manifestation of any endocrine, allergic, dermatological, hepatic, renal, hematological, pulmonary, GI, neurological or psychiatric disorder, malignancy (with the exception of treated basal cell carcinomas), or any other condition that would prevent the individual from participating in the study due to risk to the scientific validity of study assessments or to personal well-being of the patient. Participated in another clinical study that includes an investigational drug or a biologic therapy within 30 days or 5 half-lives, whichever time period is longer, prior to Visit 1 Screen.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Aldafermin (NGM282)<br>Aldafermin (NGM282) is an investigational medication. It is an engineered analog of FGF-19 which reduces synthesis of bile acids and diarrhea caused by elevated bile acids. Participants receive aldafermin (NGM282) 1 mg given by subcutaneous injection once daily for 28 days. | Drug: Aldafermin<br>* 1 mg solution<br>* Other names: NGM282;|
| Placebo Comparator: Placebo<br>A placebo looks exactly like the study drug but contains no active ingredients. It is used to learn if the effects seen are truly from the study drug. Participants receive placebo solution matching aldafermin (NGM282) given by subcutaneous injection once daily for 28 days. | Drug: Placebo<br>* Aldafermin placebo solution<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fasting Serum C4 Levels | Fasting serum C4 is measured by liquid chromatography-mass spectrometry. | 28 days | 
| Change in Stool Consistency From Baseline to Day 28 | Stool consistency as reported by the patient in daily bowel pattern diaries. Stool consistency is based on Bristol Stool Form Scale (BSFS) 1: Hard lumps; 2:Lumpy sausage; 3: Cracked sausage; 4: Smooth sausage; 5: Soft lumps; 6: Mushy; 7: Watery. spectrometry. | Baseline, 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Stool Consistency | Stool consistency as reported by the patient in daily bowel pattern diaries. Stool consistency is based on Bristol Stool Form Scale (BSFS) 1: Hard lumps; 2:Lumpy sausage; 3: Cracked sausage; 4: Smooth sausage; 5: Soft lumps; 6: Mushy; 7: Watery. | 14 days, 28 days | 
| Abdominal Pain Score | Abdominal pain rated by patient using an 11-point scale, 0 to 10 inclusive with 0 as none and 10 as worst imaginable abdominal pain. | baseline, 28 days | 
| Bowel Movements | The total number of bowel movements per day reported by the participant in the daily bowel pattern diary. | baseline, 28 days | 
| Proportion of Fecal Secretory (CDCA + DCA) Bile Acid as Measured in a Random Stool Sample by a Validated Laboratory Assay. | Fecal secretory bile acids are expressed as a percentage of the total bile acids as measured by high performance liquid chromatography-mass spectrometry. | Baseline, 14 days, 28 days | 
| Proportion of Fecal Primary (CDCA + CA) Bile Acid as Measured in a Random Stool Sample by a Validated Laboratory Assay. | Fecal primary bile acids are expressed as a percentage of the total bile acids as measured by high performance liquid chromatography-mass spectrometry. | Baseline,14 days, 28 days | 
| Total Fecal Bile Acid Concentration in a Random Stool Sample as Measured by a Validated Laboratory Assay. | Total fecal bile acids concentration in micromoles of bile acid per gram stool as measured by high performance liquid chromatography-mass spectrometry. | baseline,14 days, 28 days | 
| Total Aldafermin Concentration in Serum as Measured by a Validated Laboratory Assay | Validated aldafermin concentration (PK) laboratory assay | baseline, 14 days, 28 days |