Aldafermin (NGM282) for Chronic Diarrhea Due to Bile Acid Malabsorption (BAM)
Condition: Chronic Diarrhea; Irritable Bowel Syndrome With Diarrhea; Bile Acid Malabsorption; Bile Acid Diarrhea; Bile Acid Malabsorption Syndrome Type II; Functional Diarrhea
MeSH terms: Irritable Bowel Syndrome; Malabsorption Syndromes; Syndrome; Diarrhea
Intervention: Aldafermin; Placebo
Intervention description: 1 mg solution; Aldafermin placebo solution
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Masking description: 30 participants with diarrhea and laboratory confirmed BAM will be randomized 1:1 to either aldafermin (NGM282), 1 mg, or placebo given daily by subcutaneous injection. Participants and investigators are blinded to the treatment.
Enrollment: 30.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: No

Summary:

      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).
    

Eligibility criteria:

        Inclusion Criteria:

          1. Aged 18 to 75 years, inclusive at Visit 1 Screen.

          2. Clinical diagnosis of functional diarrhea or IBS with diarrhea according to Rome III
             or IV criteria at Visit 1 Screen.

          3. 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

          4. Body mass index (BMI) 18.0 to 45.0 kg/m2, inclusive at Visit 1 Screen

          5. Understands the study procedures, is willing and able to comply with the study
             procedures, and is able to give informed consent

          6. 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.

          7. 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:

          1. Pregnant or lactating

          2. Structural or metabolic diseases/conditions that affect the gastrointestinal system

          3. 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

          4. Use of CNS stimulant medications, including methylphenidate, atomoxetine, modafinil,
             amphetamines or phentermine.

          5. Clinically relevant changes in dietary, lifestyle, or exercise regimen within 30 days
             prior to Visit 1 Screen and throughout the duration of the study

          6. 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.

          7. .History of colorectal cancer, inflammatory bowel disease, diverticulitis, ischemic
             colitis, microscopic colitis or celiac disease

          8. History of organic abnormalities of the GI tract, intestinal obstruction, stricture,
             toxic megacolon, GI perforation, or impaired intestinal circulation.

          9. Other GI diseases such as GI bleeding or ulcerations

         10. History of cerebrovascular disease including stroke, TIA, acute coronary syndrome,
             myocardial infarction or unstable angina

         11. 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

         12. 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

         13. Clinically significant renal insufficiency including serum creatinine > 2.5 mg/dL at
             Visit 1 Screen

         14. History of severe head injury or history of seizures

         15. 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.

         16. History of alcohol use disorder or substance use disorder within 2 years of Visit 1
             Screen.

         17. 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.

         18. 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.