Bile Acid Diarrhea, Bile Acid Malabsorption, Bile Acid Malabsorption Syndrome Type II, Chronic Diarrhea, Functional Diarrhea, Irritable Bowel Syndrome With Diarrhea
Conditions
Brief 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).
Detailed description
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.
Interventions
DRUGAldafermin
1 mg solution
DRUGPlacebo
Aldafermin placebo solution
Sponsors
NGM Biopharmaceuticals, Inc
Michael Camilleri, MD
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, 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.
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Fasting Serum C4 Levels | 28 days | Fasting serum C4 is measured by liquid chromatography-mass spectrometry. |
| Change in Stool Consistency From Baseline to Day 28 | Baseline, 28 days | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Bowel Movements | baseline, 28 days | The total number of bowel movements per day reported by the participant in the daily bowel pattern diary. |
| Proportion of Fecal Secretory (CDCA + DCA) Bile Acid as Measured in a Random Stool Sample by a Validated Laboratory Assay. | Baseline, 14 days, 28 days | Fecal secretory bile acids are expressed as a percentage of the total bile acids as measured by high performance liquid chromatography-mass spectrometry. |
| Stool Consistency | 14 days, 28 days | 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. |
| Total Fecal Bile Acid Concentration in a Random Stool Sample as Measured by a Validated Laboratory Assay. | baseline,14 days, 28 days | Total fecal bile acids concentration in micromoles of bile acid per gram stool as measured by high performance liquid chromatography-mass spectrometry. |
| Total Aldafermin Concentration in Serum as Measured by a Validated Laboratory Assay | baseline, 14 days, 28 days | Validated aldafermin concentration (PK) laboratory assay |
| Proportion of Fecal Primary (CDCA + CA) Bile Acid as Measured in a Random Stool Sample by a Validated Laboratory Assay. | Baseline,14 days, 28 days | Fecal primary bile acids are expressed as a percentage of the total bile acids as measured by high performance liquid chromatography-mass spectrometry. |
| Abdominal Pain Score | baseline, 28 days | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Aldafermin (NGM282) 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 received aldafermin (NGM282) 1 mg given by subcutaneous injection once daily for 28 days.
Aldafermin: 1 mg solution | 15 |
| Placebo 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 received placebo solution matching aldafermin (NGM282) given by subcutaneous injection once daily for 28 days.
Placebo: Aldafermin placebo solution | 15 |
| Total | 30 |
Baseline characteristics
| Characteristic | Placebo | Total | Aldafermin (NGM282) |
|---|---|---|---|
| Age, Continuous | 43.0 years | 43.0 years | 49.0 years |
| Race and Ethnicity Not Collected | — | 0 Participants | — |
| Region of Enrollment United States | 15 participants | 30 participants | 15 participants |
| Sex: Female, Male Female | 14 Participants | 26 Participants | 12 Participants |
| Sex: Female, Male Male | 1 Participants | 4 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 15 | 0 / 15 |
| other Total, other adverse events | 14 / 15 | 7 / 15 |
| serious Total, serious adverse events | 1 / 15 | 0 / 15 |
Outcome results
Primary
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.
Time frame: Baseline, 28 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Aldafermin (NGM282) | Change in Stool Consistency From Baseline to Day 28 | -0.4 score on a scale |
| Placebo | Change in Stool Consistency From Baseline to Day 28 | -0.02 score on a scale |
Primary
Fasting Serum C4 Levels
Fasting serum C4 is measured by liquid chromatography-mass spectrometry.
Time frame: 28 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Aldafermin (NGM282) | Fasting Serum C4 Levels | 2.2 ng/ML |
| Placebo | Fasting Serum C4 Levels | 50.4 ng/ML |
Secondary
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.
Time frame: baseline, 28 days
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Aldafermin (NGM282) | Abdominal Pain Score | Baseline | 0.9 score on a scale |
| Aldafermin (NGM282) | Abdominal Pain Score | Day 28 | 0.6 score on a scale |
| Placebo | Abdominal Pain Score | Baseline | 0.4 score on a scale |
| Placebo | Abdominal Pain Score | Day 28 | 0.5 score on a scale |
Secondary
Bowel Movements
The total number of bowel movements per day reported by the participant in the daily bowel pattern diary.
Time frame: baseline, 28 days
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Aldafermin (NGM282) | Bowel Movements | Baseline | 2.3 bowel movements per day |
| Aldafermin (NGM282) | Bowel Movements | Day 28 | 2.3 bowel movements per day |
| Placebo | Bowel Movements | Baseline | 2.3 bowel movements per day |
| Placebo | Bowel Movements | Day 28 | 2.1 bowel movements per day |
Secondary
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.
Time frame: Baseline,14 days, 28 days
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Aldafermin (NGM282) | Proportion of Fecal Primary (CDCA + CA) Bile Acid as Measured in a Random Stool Sample by a Validated Laboratory Assay. | Baseline | 5.4 percentage of the total bile acids |
| Aldafermin (NGM282) | Proportion of Fecal Primary (CDCA + CA) Bile Acid as Measured in a Random Stool Sample by a Validated Laboratory Assay. | Day 14 | 10.3 percentage of the total bile acids |
| Aldafermin (NGM282) | Proportion of Fecal Primary (CDCA + CA) Bile Acid as Measured in a Random Stool Sample by a Validated Laboratory Assay. | Day 28 | 9.9 percentage of the total bile acids |
| Placebo | Proportion of Fecal Primary (CDCA + CA) Bile Acid as Measured in a Random Stool Sample by a Validated Laboratory Assay. | Baseline | 5.2 percentage of the total bile acids |
| Placebo | Proportion of Fecal Primary (CDCA + CA) Bile Acid as Measured in a Random Stool Sample by a Validated Laboratory Assay. | Day 14 | 2.8 percentage of the total bile acids |
| Placebo | Proportion of Fecal Primary (CDCA + CA) Bile Acid as Measured in a Random Stool Sample by a Validated Laboratory Assay. | Day 28 | 14.3 percentage of the total bile acids |
Secondary
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.
Time frame: Baseline, 14 days, 28 days
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Aldafermin (NGM282) | Proportion of Fecal Secretory (CDCA + DCA) Bile Acid as Measured in a Random Stool Sample by a Validated Laboratory Assay. | Baseline | 63.8 percentage of the total bile acids |
| Aldafermin (NGM282) | Proportion of Fecal Secretory (CDCA + DCA) Bile Acid as Measured in a Random Stool Sample by a Validated Laboratory Assay. | Day 14 | 43.2 percentage of the total bile acids |
| Aldafermin (NGM282) | Proportion of Fecal Secretory (CDCA + DCA) Bile Acid as Measured in a Random Stool Sample by a Validated Laboratory Assay. | Day 28 | 45.5 percentage of the total bile acids |
| Placebo | Proportion of Fecal Secretory (CDCA + DCA) Bile Acid as Measured in a Random Stool Sample by a Validated Laboratory Assay. | Baseline | 63.2 percentage of the total bile acids |
| Placebo | Proportion of Fecal Secretory (CDCA + DCA) Bile Acid as Measured in a Random Stool Sample by a Validated Laboratory Assay. | Day 14 | 59.2 percentage of the total bile acids |
| Placebo | Proportion of Fecal Secretory (CDCA + DCA) Bile Acid as Measured in a Random Stool Sample by a Validated Laboratory Assay. | Day 28 | 60.0 percentage of the total bile acids |
Secondary
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.
Time frame: 14 days, 28 days
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Aldafermin (NGM282) | Stool Consistency | Day 14 | 4.6 score on a scale |
| Aldafermin (NGM282) | Stool Consistency | Day 28 | 4.4 score on a scale |
| Placebo | Stool Consistency | Day 14 | 4.8 score on a scale |
| Placebo | Stool Consistency | Day 28 | 5.1 score on a scale |
Secondary
Total Aldafermin Concentration in Serum as Measured by a Validated Laboratory Assay
Validated aldafermin concentration (PK) laboratory assay
Time frame: baseline, 14 days, 28 days
Population: Data was not collected nor analyzed
Secondary
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.
Time frame: baseline,14 days, 28 days
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Aldafermin (NGM282) | Total Fecal Bile Acid Concentration in a Random Stool Sample as Measured by a Validated Laboratory Assay. | Baseline | 3.1 mmol/g |
| Aldafermin (NGM282) | Total Fecal Bile Acid Concentration in a Random Stool Sample as Measured by a Validated Laboratory Assay. | Day 14 | 0.5 mmol/g |
| Aldafermin (NGM282) | Total Fecal Bile Acid Concentration in a Random Stool Sample as Measured by a Validated Laboratory Assay. | Day 28 | 0.5 mmol/g |
| Placebo | Total Fecal Bile Acid Concentration in a Random Stool Sample as Measured by a Validated Laboratory Assay. | Baseline | 3.5 mmol/g |
| Placebo | Total Fecal Bile Acid Concentration in a Random Stool Sample as Measured by a Validated Laboratory Assay. | Day 14 | 2.7 mmol/g |
| Placebo | Total Fecal Bile Acid Concentration in a Random Stool Sample as Measured by a Validated Laboratory Assay. | Day 28 | 3.6 mmol/g |