Treatment of Bile Acid Diarrhoea With Atorvastatin (BASTA): A Randomised, Double-Blind, Placebo-Controlled, Crossover, Investigator-Initiated Trial
试验速览
- 阶段
- 4 期
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 20
- 试验地点
- 1
- 主要终点
- Reduction in bile acid synthesis measured via 7alpha-Hydroxy-4-cholesten-3-on (C4)
研究概览
简要总结
Bile acid diarrhoea (BAD) is a socially debilitating disease with stomach pain, high stool frequency, urgency, and faecal incontinence as the main symptoms. Studies estimate that 1-2% of the population suffers from the disease.
There is an unmet need for more treatment options in patients suffering from BAD.
The investigators hypothesise that atorvastatin treatment lowers bile acid synthesis in patients with bile acid diarrhoea. The investigators will investigate this hypothesis in the current study, BASTA, which is a Randomised, Double-Blind, Placebo-Controlled, Crossover, Proof of Concept, Investigator-Initiated, Trial.
详细描述
Bile acid diarrhoea (BAD) is a socially debilitating disease with stomach pain, high stool frequency, urgency, and faecal incontinence as the main symptoms. Studies estimate that 1-2% of the population suffers from the disease.
Bile acids are synthesised from cholesterol in hepatocytes through a tightly regulated enzymatic process and then excreted to the gut lumen in response to food ingestion. In a healthy individual 95 % of the bile acids are recycled in the enterohepatic circulation in a tightly regulated process. BAD symptoms arise due to a pathological spill-over of bile acids to the colon.
Currently, individuals with BAD are typically treated with bile acids sequestrants. However, only about 2/3 patients experience an improvement in their symptoms on this treatment. Thus, the possibility of yet another tool in the toolbox is compelling.
Statins are used by millions of patients world-wide to reduce their risk of cardiovascular morbidity and mortality and are considered safe with overall mild and benign adverse effects. Statins lower the intracellular levels of cholesterol in hepatocytes. As such, atorvastatin could potentially reduce the bile acid production in individuals with BAD leading to a reduction or normalisation of the amount of bile acids secreted to the intestinal lumen and entering the colon. Unpublished results from the investigators' group show a 43 % reduction of serum C4, a biomarker of bile acid synthesis which can also be used to diagnose BAD, in healthy, young men, who were treated with atorvastatin for 14 days (7 days of 40 mg atorvastatin once daily followed by 7 days of 80 mg atorvastatin once daily) compared to placebo treatment.
The investigators hypothesise that atorvastatin treatment lowers bile acid synthesis in patients with bile acid diarrhoea.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •age 18 years or above
- •Self-identification as White
- •Confirmed moderate-severe bile acid diarrhoea with a SeHCAT test result of ≤ 10 %
- •Reported number of average daily stools ≥ 3 stools per day
- •Reported number of average daily watery (6 or 7 on the Bristol Stool Chart) stools ≥ 1 stools per day(30)
- •Informed and written consent
排除标准
- •Unwillingness to pause any of the following medications during the trial: bile acid sequestrants, morphine medication, liraglutide or anti-constipation medication (e.g., lactulose, laxoberal, magnesia)
- •Unwillingness to pause any anti-diarrhoea medication (e.g., imodium) from 3 days before initiation of each stool diary until after the respective visit
- •If regularly administering psyllium or metformin, unwillingness to agree to a stable dose of psyllium or metformin throughout the trial
- •Concomitant use of any drug in the GLP-1 receptor agonist drug class with the exception of paused liraglutide, see above
- •Concomitant use of any kind of insulin medication
- •Planned major changes in food consumption throughout the trial, including planned weight loss attempts
- •Prior use of any statin within the recent 6 months
- •Intake of larger quantities of grapefruit juice during trial participation, at the discretion of the investigator
- •History of/present hepatobiliary disorder (except for simple metabolic dysfunction-associated fatty liver disease) and/or alanine aminotransferase and/or serum aspartate aminotransferase ≥ 3 times upper limit of normal
- •Crohn's disease, ulcerative colitis, celiac disease or lactose intolerance
- •Previous intestinal resection or major intra-abdominal surgery incl. stoma (cholecystectomy and appendectomy not included)
- •Nephropathy with estimated glomerular filtration rate < 45 ml/min/1,73 m2
- •Plasma level of creatine kinase ≥ 5 times the upper limit of normal
- •A recent stroke or transient ischemic attack (within 6 months)
- •Any treatment or condition requiring acute or subacute medical or surgical intervention
- •Hypothyroidism or hyperthyroidism, if not well regulated, at the discretion of the investigator
- •Active or recent (within 6 months) clinically significant malignant disease (non-melanoma skin cancer not included), at the discretion of the investigator
- •Alcohol consumption exceeding 12 units/week for women or 18 units/week for men, respectively. These thresholds are based on the limits of the European Association for the Study of the Liver
- •Drug abuse, at the discretion of the investigator
- •Fertile women not using any of the following contraceptive methods for the duration of the trial until at least 5 days after end of trial: Hormonal (tablet/pill, depot injection of progesterone, subdermal gestagen implantation, hormone intrauterine devices (IUD), hormonal vaginal ring or transdermal hormonal patch) associated with inhibition of ovulation, chemical (copper IUD), sterilisation, vasectomised partner with a confirmatory test, or sexual abstinence per the investigator's discretion
- •Pregnant or nursing women
- •Known or suspected hypersensitivity to atorvastatin or any of the additives in the tablet
- •Receipt of any investigational drug within 30 days prior to visit 0
- •Concomitant treatment with any of the following (topical administration not included): ciclosporin, telithromycin, clarithromycin, delavirdin, stiripentol, ketoconazol, voriconazol, itraconazol, posaconazol, letermovir, ritonavir, lopinavir, atazanavir, indinavir, darunavir, bocepravir, telaprevir, elbasvir/grazoprevir, ledipasvir/sofosbuvir, erythromycin, niacin, ezetimibe, fusidic acid, gemfibrozil, colchicine, digoxin, warfarin
- •Unable to speak or understand Danish or mental incapacity that preclude adequate understanding or cooperation or unwillingness to comply with trial requirements
- •Active participation in any other clinical intervention trial (observational studies not included)
- •Other concomitant disease or treatment that according to the investigator's assessment makes the person unsuitable for study participation
研究组 & 干预措施
Atorvastatin
40 mg Atorvastatin tablets are manufactored by the Central Pharmacy of the Capital Region of Denmark and are identical to the placebo tablets except containing the active ingredient (atorvastatin). Participants will be administering one tablet for two weeks followed by two tablets for two weeks (80 mg atorvastatin). Then four weeks of washout before entering the placebo arm (crossover).
干预措施: Atorvastatin (Drug)
Placebo
Placebo tablets are manufactored by the Central Pharmacy of the Capital Region of Denmark and are identical to the IMP except with the active ingredient (atorvastatin) omitted. Participants will be administering one tablet for two weeks followed by two tablets for two weeks. Then four weeks of washout before entering the atorvastatin arm (crossover).
干预措施: Placebo (Drug)
结局指标
主要结局
Reduction in bile acid synthesis measured via 7alpha-Hydroxy-4-cholesten-3-on (C4)
时间窗: The end of week 4 and the end of week 12.
Ratio of geometric mean concentration of 7alpha-Hydroxy-4-cholesten-3-on (C4) at the end of the 80 mg atorvastatin treatment period compared to the end of the placebo treatment period.
次要结局
- Reduction in bile acid synthesis measured via C4(The end of week 4 and the end of week 12.)
- Cholesterol metabolism(The end of week 4 and the end of week 12.)
- Reduction in BAD symptoms measured via a stool diary.(Week 4 and week 12.)
- A reduction in BAD symptoms measured via a stool diary.(Week 4 and week 12.)
- Symptom severity measured via IBS-SSS(The end of week 4 and the end of week 12.)
- Reduction in bile acid synthesis measured via C4.(The end of week 4 and the end of week 12.)
- Bile acid metabolism measured via FGF-19(The end of week 4 and the end of week 12.)
- Bile acid metabolism measured via blood levels of total bile acids(The end of week 4 and the end of week 12.)
- Bile acid levels measured in stool samples(The end of week 4 and the end of week 12.)
研究者
Asger Lund, MD
MD, PhD
University Hospital, Gentofte, Copenhagen