{"product_id":"elafibranor-for-primary-biliary-cholangitis-a-comprehensive-review-of-the-elative-phase-3-trial","title":"Elafibranor for Primary Biliary Cholangitis: A Comprehensive Review of the ELATIVE Phase 3 Trial","description":"\u003cp\u003eIn a phase 3 clinical trial of 161 patients with primary biliary cholangitis who did not respond adequately to the standard first-line drug ursodeoxycholic acid, treatment with the experimental drug elafibranor (80 mg once daily) produced a biochemical response in 51% of patients compared with only 4% of those taking placebo at 52 weeks — a difference of 47 percentage points that was highly statistically significant (P\u0026lt;0.001). Alkaline phosphatase levels normalized in 15% of elafibranor-treated patients versus none in the placebo group (P=0.002). However, the drug did not significantly reduce itch intensity in patients with moderate-to-severe pruritus, and it caused more gastrointestinal side effects such as abdominal pain, diarrhea, nausea, and vomiting.\u003c\/p\u003e\n\n\u003ch1\u003eElafibranor for Primary Biliary Cholangitis: A Comprehensive Review of the ELATIVE Phase 3 Trial\u003c\/h1\u003e\n\n\u003ch2\u003eTable of Contents\u003c\/h2\u003e\n\u003cul\u003e\n\u003cli\u003e\u003ca href=\"#ddn-key-points\"\u003eKey Points\u003c\/a\u003e\u003c\/li\u003e\n\n\u003cli\u003e\u003ca href=\"#background\"\u003eBackground: What Is Primary Biliary Cholangitis?\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#current-treatments\"\u003eCurrent Treatments and Their Limitations\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#what-is-elafibranor\"\u003eWhat Is Elafibranor and How Does It Work?\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#study-methods\"\u003eHow Was the ELATIVE Trial Conducted?\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#trial-endpoints\"\u003eWhat Did the Trial Measure?\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#patient-population\"\u003eWho Participated in the Trial?\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#primary-results\"\u003ePrimary Results: Biochemical Response\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#secondary-results\"\u003eSecondary Results: Alkaline Phosphatase Normalization\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#itch-results\"\u003eResults for Itch (Pruritus)\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#other-results\"\u003eOther Secondary Findings\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#safety\"\u003eSafety and Side Effects\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#statistical-methods\"\u003eHow the Data Were Analyzed\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#clinical-implications\"\u003eWhat These Results Mean for Patients\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#limitations\"\u003eLimitations of the Study\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#recommendations\"\u003eRecommendations and Next Steps\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#ddn-faq\"\u003eFrequently Asked Questions\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#source\"\u003eSource Information\u003c\/a\u003e\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003c!-- ddn:keypoints:start --\u003e\n\u003ch2 id=\"ddn-key-points\"\u003eKey Points\u003c\/h2\u003e\n\u003cul\u003e\n\u003cli\u003eIn a 161-patient trial, 51% on elafibranor achieved a biochemical response at 52 weeks versus 4% on placebo.\u003c\/li\u003e\n\u003cli\u003eAlkaline phosphatase normalized in 15% on elafibranor versus none on placebo.\u003c\/li\u003e\n\u003cli\u003eElafibranor did not significantly reduce itch intensity as measured by the WI-NRS.\u003c\/li\u003e\n\u003cli\u003eCommon side effects were gastrointestinal: abdominal pain, diarrhea, nausea, and vomiting; most were mild or moderate.\u003c\/li\u003e\n\u003cli\u003eLonger-term data are needed to confirm whether biochemical improvements reduce cirrhosis, transplant, or death.\u003c\/li\u003e\n\u003c\/ul\u003e\n\u003c!-- ddn:keypoints:end --\u003e\n\n\n\u003ch2 id=\"background\"\u003eBackground: What Is Primary Biliary Cholangitis?\u003c\/h2\u003e\n\n\u003cp\u003ePrimary biliary cholangitis (PBC) is a rare, chronic liver disease that occurs when the body's immune system attacks the small bile ducts inside the liver. The disease destroys the interlobular bile ducts. These are the tiny tubes that carry bile out of the liver. This leads to a buildup of bile in the liver, a condition called cholestasis. Eventually it leads to liver scarring (fibrosis).\u003c\/p\u003e\n\n\u003cp\u003eThe disease occurs predominantly in women aged 40 years and older, and its prevalence is increasing worldwide. If left untreated, primary biliary cholangitis can progress to cirrhosis (permanent scarring of the liver), the need for a liver transplant, and premature death.\u003c\/p\u003e\n\n\u003cp\u003eDoctors use two key blood tests to track how the disease is progressing: \u003cstrong\u003ealkaline phosphatase\u003c\/strong\u003e (an enzyme that rises when bile ducts are damaged) and \u003cstrong\u003ebilirubin\u003c\/strong\u003e (a yellow pigment produced when red blood cells break down). Higher levels of these markers are correlated with a higher risk of poor outcomes. Doctors use these markers as prognostic indicators. This means they help predict how the disease will develop over time.\u003c\/p\u003e\n\n\u003ch2 id=\"current-treatments\"\u003eCurrent Treatments and Their Limitations\u003c\/h2\u003e\n\n\u003cp\u003eThe only approved first-line therapy for patients with primary biliary cholangitis is \u003cstrong\u003eursodeoxycholic acid\u003c\/strong\u003e (UDCA), a tertiary hydrophilic bile acid. This medication helps move bile through the liver and reduces its toxic effects.\u003c\/p\u003e\n\n\u003cp\u003eHowever, ursodeoxycholic acid does not work well enough for everyone. Up to 40% of patients have an inadequate response to this treatment, and 3 to 5% of patients experience unacceptable adverse events (side effects) that force them to stop taking it.\u003c\/p\u003e\n\n\u003cp\u003eFor patients who cannot tolerate or do not respond adequately to ursodeoxycholic acid, the only approved second-line treatment is \u003cstrong\u003eobeticholic acid\u003c\/strong\u003e, a selective farnesoid X receptor agonist. But this drug also has limitations. Fewer than 50% of patients achieve a biochemical response. The drug may worsen pruritus (itching). Pruritus is already a common and distressing symptom of primary biliary cholangitis.\u003c\/p\u003e\n\n\u003cp\u003eSome doctors have used fibrates (a class of drugs normally used to lower cholesterol) as an off-label second-line therapy. These drugs have shown potential for improving biochemical response and decreasing pruritus in patients with primary biliary cholangitis. However, an efficacious and safe long-term treatment remains an unmet need for this patient population.\u003c\/p\u003e\n\n\u003ch2 id=\"what-is-elafibranor\"\u003eWhat Is Elafibranor and How Does It Work?\u003c\/h2\u003e\n\n\u003cp\u003eElafibranor is an oral medication that acts as a dual peroxisome proliferator-activated receptor (PPAR) alpha and delta agonist. In simpler terms, elafibranor activates two specific receptor proteins in the body — PPAR-alpha and PPAR-delta — which then modulate (adjust) the activity of certain genes.\u003c\/p\u003e\n\n\u003cp\u003eThrough this downstream modulation of nuclear receptor targets, elafibranor decreases the toxic effects of bile acids and reduces inflammation in the liver.\u003c\/p\u003e\n\n\u003cp\u003eBefore this phase 3 trial, a 12-week phase 2 trial involving patients with primary biliary cholangitis showed that treatment with elafibranor significantly reduced biomarkers of disease activity. No safety concerns were identified in that earlier study. The ELATIVE trial was designed to confirm those findings in a larger, more rigorous study.\u003c\/p\u003e\n\n\u003ch2 id=\"study-methods\"\u003eHow Was the ELATIVE Trial Conducted?\u003c\/h2\u003e\n\n\u003cp\u003eThe ELATIVE trial was a multinational, phase 3, double-blind, placebo-controlled trial. \"Double-blind\" means that neither the patients nor their doctors knew which treatment each patient was receiving. \"Placebo-controlled\" means that one group of patients received an inactive pill (placebo) for comparison.\u003c\/p\u003e\n\n\u003cp\u003eThe trial enrolled patients 18 to 75 years of age. These patients had received a diagnosis of primary biliary cholangitis. They had had an inadequate response to ursodeoxycholic acid or unacceptable side effects with ursodeoxycholic acid. The trial was conducted at 82 sites in 14 countries.\u003c\/p\u003e\n\n\u003cp\u003eKey inclusion criteria required patients to have an alkaline phosphatase level at least 1.67 times the upper limit of the normal range. That upper limit is 174 U per liter for women and 215 U per liter for men. Patients also needed a total bilirubin level no more than 2 times the upper limit of normal. That upper limit is 41 micromoles per liter.\u003c\/p\u003e\n\n\u003cp\u003ePatients were excluded if they had autoimmune hepatitis or primary biliary cirrhosis–autoimmune hepatitis overlap, or if they had evidence of clinically significant hepatic decompensation (liver failure).\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eTrial design:\u003c\/strong\u003e Patients were randomly assigned in a 2:1 ratio to receive either once-daily elafibranor at a dose of 80 mg or placebo. This means that for every 2 patients who received elafibranor, 1 patient received placebo. Randomization was stratified (balanced) according to two factors:\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003eWhether the patient's alkaline phosphatase level was greater than 3 times the upper limit of normal or their total bilirubin level was above the upper limit of normal (yes or no)\u003c\/li\u003e\n\u003cli\u003eWhether the patient's score on the Worst Itch Numeric Rating Scale (WI-NRS) was greater than or equal to 4 (yes or no). The WI-NRS is a scale where patients rate their worst itching from 0 (no itch) to 10 (worst itch imaginable)\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003ePatients who were already receiving a stable dose of ursodeoxycholic acid were permitted to continue this treatment throughout the trial.\u003c\/p\u003e\n\n\u003cp\u003eThe double-blind period had two parts. In part one, patients received their assigned treatment (elafibranor or placebo) in a double-blind manner for at least 52 weeks. In part two, patients continued their assigned regimen after week 52 until all patients had completed their week 52 assessment, or for a maximum of 104 weeks, whichever came first.\u003c\/p\u003e\n\n\u003cp\u003eAfter the double-blind period ended, patients could enter an open-label extension period and receive elafibranor for up to 5 additional years.\u003c\/p\u003e\n\n\u003cp\u003eThe trial was designed by a steering group of clinical experts and representatives from the sponsors (GENFIT and Ipsen). The investigators gathered the data, and data analyses were performed by the sponsors. The trial followed International Council for Harmonisation Good Clinical Practice guidelines, applicable regulatory requirements, and the principles of the Declaration of Helsinki. All patients provided written informed consent.\u003c\/p\u003e\n\n\u003ch2 id=\"trial-endpoints\"\u003eWhat Did the Trial Measure?\u003c\/h2\u003e\n\n\u003cp\u003eThe \u003cstrong\u003eprimary end point\u003c\/strong\u003e was a biochemical response at week 52. A patient was considered to have achieved a biochemical response if they met all three of the following criteria:\u003c\/p\u003e\n\n\u003col\u003e\n\u003cli\u003eAn alkaline phosphatase level less than 1.67 times the upper limit of the normal range\u003c\/li\u003e\n\u003cli\u003eA reduction of at least 15% in alkaline phosphatase from baseline (the starting level)\u003c\/li\u003e\n\u003cli\u003eTotal bilirubin at or below the upper limit of normal\u003c\/li\u003e\n\u003c\/ol\u003e\n\n\u003cp\u003eThe \u003cstrong\u003ekey secondary end points\u003c\/strong\u003e were:\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003eNormalization of the alkaline phosphatase level at week 52\u003c\/li\u003e\n\u003cli\u003eOne measure was a change in pruritus (itch) intensity from baseline through week 52 and through week 24. This change was measured on the WI-NRS among patients with moderate-to-severe pruritus. Moderate-to-severe pruritus was defined as a WI-NRS score of 4 or higher at baseline.\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003e\u003cstrong\u003eOther secondary end points\u003c\/strong\u003e included changes from baseline to week 52 in several measures:\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003ePatient-reported outcomes related to pruritus, assessed with the primary biliary cirrhosis–40 (PBC-40) questionnaire and the 5-D itch scale\u003c\/li\u003e\n\u003cli\u003eLevels of alkaline phosphatase, total bilirubin, albumin, gamma-glutamyltransferase, alanine aminotransferase, aspartate aminotransferase, IgG, and IgM\u003c\/li\u003e\n\u003cli\u003eThe international normalized ratio (a measure of blood clotting)\u003c\/li\u003e\n\u003cli\u003eThe enhanced liver fibrosis score is calculated from three markers of liver fibrosis. These markers are hyaluronic acid, procollagen type III amino-terminal peptide, and tissue inhibitor of matrix metalloproteinase-1. A score below 7.7 indicates no-to-mild fibrosis.\u003c\/li\u003e\n\u003cli\u003eLiver stiffness, as measured by transient elastography (FibroScan; scores range from 2 to 75 kPa, with higher values indicating greater liver stiffness)\u003c\/li\u003e\n\u003cli\u003eBiomarkers of bile acid synthesis (7-alpha-hydroxy-4-cholesten-3-one and fibroblast growth factor 19)\u003c\/li\u003e\n\u003cli\u003eLipid variables (total cholesterol, LDL cholesterol, HDL cholesterol, VLDL cholesterol, and triglycerides)\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eThe PBC-40 questionnaire contains 40 items, each scored from 1 (or 0 for some items related to itch, social function, and symptoms) to 5, with higher scores indicating worse quality of life. The 5-D itch scale measures the degree, duration, direction, disability, and distribution of itching. Direction means improvement or worsening. Disability means effect on daily activities. Total scores range from 5 to 25. Higher scores indicate worse itch-related quality of life.\u003c\/p\u003e\n\n\u003ch2 id=\"patient-population\"\u003eWho Participated in the Trial?\u003c\/h2\u003e\n\n\u003cp\u003eFrom September 2020 through June 2022, a total of 161 patients were randomly assigned to receive elafibranor (108 patients) or placebo (53 patients). These patients made up both the intention-to-treat population (all patients who were randomized) and the safety population (all patients who received at least one dose).\u003c\/p\u003e\n\n\u003cp\u003eThe intention-to-treat population of patients with moderate-to-severe pruritus at baseline included 66 patients (44 in the elafibranor group and 22 in the placebo group).\u003c\/p\u003e\n\n\u003cp\u003ePatient demographics and clinical characteristics at baseline were similar between the two groups. Here is a detailed breakdown:\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003e\n\u003cstrong\u003eAge:\u003c\/strong\u003e The mean age was 57.1 years (standard deviation ±8.7 years). In the elafibranor group, the mean age was 57.5 ± 8.4 years; in the placebo group, it was 56.4 ± 9.3 years.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eSex:\u003c\/strong\u003e Overall, 96% of patients were women (154 of 161). In the elafibranor group, 94% were women (102 of 108); in the placebo group, 98% were women (52 of 53).\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eRace:\u003c\/strong\u003e Overall, 91% of patients were White (147 of 161). In the elafibranor group, 94% were White (101 of 108); in the placebo group, 87% were White (46 of 53).\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eTime since diagnosis:\u003c\/strong\u003e The mean time since diagnosis was 8.0 ± 6.2 years. In the elafibranor group, it was 7.9 ± 5.9 years; in the placebo group, it was 8.3 ± 6.8 years.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eAlkaline phosphatase level:\u003c\/strong\u003e The mean baseline level was 321.9 ± 150.9 U per liter. In the elafibranor group, it was 321.3 ± 121.9 U per liter; in the placebo group, it was 323.1 ± 198.6 U per liter. Overall, 39% of patients (63 of 161) had an alkaline phosphatase level greater than 3 times the upper limit of normal.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eTotal bilirubin level:\u003c\/strong\u003e The mean baseline level was 9.6 ± 5.1 micromoles per liter. In the elafibranor group, it was 9.7 ± 5.1 micromoles per liter; in the placebo group, it was 9.4 ± 5.0 micromoles per liter.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eAspartate aminotransferase level:\u003c\/strong\u003e The mean baseline level was 45.7 ± 27.2 U per liter. In the elafibranor group, it was 45.0 ± 24.2 U per liter; in the placebo group, it was 47.2 ± 32.8 U per liter.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eAlanine aminotransferase level:\u003c\/strong\u003e The mean baseline level was 49.6 ± 32.6 U per liter. In the elafibranor group, it was 49.3 ± 29.4 U per liter; in the placebo group, it was 50.3 ± 38.7 U per liter.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eGamma-glutamyltransferase level:\u003c\/strong\u003e The mean baseline level was 215.5 ± 197.4 U per liter. In the elafibranor group, it was 213.3 ± 186.1 U per liter; in the placebo group, it was 220.0 ± 220.3 U per liter.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eConcurrent ursodeoxycholic acid use:\u003c\/strong\u003e Overall, 95% of patients (153 of 161) were taking ursodeoxycholic acid at baseline. In the elafibranor group, 94% (102 of 108) were taking it; in the placebo group, 96% (51 of 53) were taking it.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eWI-NRS score:\u003c\/strong\u003e The mean baseline score was 3.3 ± 2.8. In the elafibranor group, it was 3.3 ± 2.8; in the placebo group, it was 3.2 ± 2.9. Overall, 41% of patients (66 of 161) had moderate-to-severe pruritus (WI-NRS score of 4 or higher).\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eLiver stiffness:\u003c\/strong\u003e The mean baseline liver stiffness was 10.1 ± 8.2 kPa. In the elafibranor group, it was 9.9 ± 7.8 kPa; in the placebo group, it was 10.7 ± 8.9 kPa. Overall, 31% of patients (48 of 154) had liver stiffness greater than 10.0 kPa.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eBridging fibrosis or cirrhosis:\u003c\/strong\u003e Among patients who underwent a liver biopsy, 43% (20 of 47) had bridging fibrosis or cirrhosis. In the elafibranor group, 39% (12 of 31) had bridging fibrosis or cirrhosis; in the placebo group, 50% (8 of 16) had bridging fibrosis or cirrhosis.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eLiver stiffness greater than 10 kPa or bridging fibrosis (or both) or cirrhosis:\u003c\/strong\u003e Overall, 35% of patients (54 of 154) met this composite criterion. In the elafibranor group, 34% (35 of 104) met this criterion; in the placebo group, 38% (19 of 50) met this criterion.\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003ch2 id=\"primary-results\"\u003ePrimary Results: Biochemical Response\u003c\/h2\u003e\n\n\u003cp\u003eAt week 52, a biochemical response (the primary end point) was observed in a significantly greater percentage of patients in the elafibranor group than in the placebo group. The percentage was 51% (55 of 108 patients) for elafibranor versus 4% (2 of 53 patients) for placebo. This represents a difference of 47 percentage points (95% confidence interval [CI], 32 to 57; P\u0026lt;0.001).\u003c\/p\u003e\n\n\u003cp\u003eThe P value of less than 0.001 means there is less than a 0.1% probability that this result occurred by chance alone. In other words, the finding is highly statistically significant.\u003c\/p\u003e\n\n\u003cp\u003eA response to elafibranor appeared to occur within 4 weeks after initiation of treatment and was maintained through 52 weeks. The results of supplementary analyses were consistent with these primary results, and subgroup analyses showed similar findings across different patient groups.\u003c\/p\u003e\n\n\u003ch2 id=\"secondary-results\"\u003eSecondary Results: Alkaline Phosphatase Normalization\u003c\/h2\u003e\n\n\u003cp\u003eNormalization of the alkaline phosphatase level at week 52 (a key secondary end point) occurred in 15% of patients in the elafibranor group and in 0% of patients in the placebo group. This represents a difference of 15 percentage points (95% CI, 6 to 23; P=0.002).\u003c\/p\u003e\n\n\u003cp\u003eThe P value of 0.002 means there is a 0.2% probability that this result occurred by chance alone — a statistically significant finding.\u003c\/p\u003e\n\n\u003cp\u003eThe percentage of patients with normalization of the alkaline phosphatase level was consistently higher in the elafibranor group through week 52 than in the placebo group. Subgroup analyses of alkaline phosphatase normalization showed similar findings across different patient groups.\u003c\/p\u003e\n\n\u003cp\u003eReductions from baseline in alkaline phosphatase levels were observed in the elafibranor group within 4 weeks after initiation of treatment. These reductions appeared to be sustained at levels lower than those in the placebo group through week 52, with a between-group estimated percentage-point difference of −40.6 ± 5.3 (95% CI, −47.8 to −33.5).\u003c\/p\u003e\n\n\u003ch2 id=\"itch-results\"\u003eResults for Itch (Pruritus)\u003c\/h2\u003e\n\n\u003cp\u003eSome patients had moderate-to-severe pruritus at baseline: 44 patients in the elafibranor group and 22 in the placebo group. Among these patients, the least-squares mean change from baseline through week 52 on the WI-NRS did not differ significantly between the groups. The change was −1.93 for elafibranor versus −1.15 for placebo. The difference was −0.78 (95% CI, −1.99 to 0.42; P=0.20).\u003c\/p\u003e\n\n\u003cp\u003eSimilarly, from baseline through week 24, the least-squares mean change in the WI-NRS score did not differ significantly between the elafibranor group and the placebo group: −1.60 versus −1.26. The difference was −0.34 (95% CI, −1.49 to 0.80).\u003c\/p\u003e\n\n\u003cp\u003eThe P value of 0.20 for the week 52 analysis means there is a 20% probability that this result occurred by chance alone. This is not statistically significant, meaning the trial did not demonstrate that elafibranor reduced itch intensity more than placebo.\u003c\/p\u003e\n\n\u003cp\u003eHowever, among patients with moderate-to-severe pruritus at baseline, the changes from baseline to week 52 appeared to favor elafibranor over placebo for two other itch-related measures:\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003eThe itch domain of the PBC-40 quality-of-life questionnaire (least-squares mean difference, −2.3; 95% CI, −4.0 to −0.7)\u003c\/li\u003e\n\u003cli\u003eThe total score on the 5-D itch scale (least-squares mean difference, −3.0; 95% CI, −5.5 to −0.5)\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eThe changes in other domains of the PBC-40 questionnaire over 52 weeks were similar in the two groups.\u003c\/p\u003e\n\n\u003ch2 id=\"other-results\"\u003eOther Secondary Findings\u003c\/h2\u003e\n\n\u003cp\u003eAt week 52, levels of 7-alpha-hydroxy-4-cholesten-3-one and fibroblast growth factor 19 appeared to be lower in patients who received elafibranor than in those who received placebo. These two substances are biomarkers of bile acid synthesis.\u003c\/p\u003e\n\n\u003cp\u003eThe levels of total cholesterol, LDL cholesterol, VLDL cholesterol, and triglycerides were lower in patients who received elafibranor than in those who received placebo within 4 weeks after baseline. Lower levels of triglycerides and VLDL cholesterol with elafibranor than with placebo were sustained through week 52. HDL cholesterol levels remained stable with elafibranor treatment from baseline through week 52.\u003c\/p\u003e\n\n\u003cp\u003eChanges from baseline to week 52 in other liver-related variables and immunoglobulins (IgG and IgM) were also measured and reported in the trial.\u003c\/p\u003e\n\n\u003ch2 id=\"safety\"\u003eSafety and Side Effects\u003c\/h2\u003e\n\n\u003cp\u003eSimilar percentages of patients in the two groups had adverse events. Similar percentages had adverse events considered to be related to the trial regimen. Similar percentages had severe or serious adverse events. Similar percentages had adverse events leading to discontinuation of elafibranor or placebo.\u003c\/p\u003e\n\n\u003cp\u003eAdverse events that occurred in more than 10% of patients and more frequently in patients receiving elafibranor than in those receiving placebo were predominantly gastrointestinal in nature. These included:\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003eAbdominal pain\u003c\/li\u003e\n\u003cli\u003eDiarrhea\u003c\/li\u003e\n\u003cli\u003eNausea\u003c\/li\u003e\n\u003cli\u003eVomiting\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eThe majority of adverse events were of mild or moderate intensity. Two patients who received elafibranor died during the clinical trial — one from postoperative complications after a surgical operation for an abdominal hernia repair, and one from biliary sepsis and acute kidney injury in a patient with end-stage liver disease — and neither death was considered related to the treatment.\u003c\/p\u003e\n\n\u003ch2 id=\"statistical-methods\"\u003eHow the Data Were Analyzed\u003c\/h2\u003e\n\n\u003cp\u003eThe trial was designed to enroll 150 patients (100 in the elafibranor group and 50 in the placebo group). This sample size would provide a power of at least 90%, at a two-sided alpha level of 0.05. This power would detect a between-group difference of 35 percentage points in the proportion of patients with a biochemical response at week 52.\u003c\/p\u003e\n\n\u003cp\u003e\"Power\" refers to the probability that the trial would detect a true difference between treatments if one exists. \"Alpha level\" refers to the threshold for statistical significance.\u003c\/p\u003e\n\n\u003cp\u003eThe primary analysis was based on data from the double-blind period, with efficacy end points assessed at week 52. Safety analyses included data up to 104 weeks.\u003c\/p\u003e\n\n\u003cp\u003eThe primary end point and key secondary end points were assessed with a prespecified fixed-sequence testing approach at a two-sided alpha of 0.05. This means the researchers tested each hypothesis in a predetermined order, stopping when a nonsignificant result was encountered. Other secondary end points are reported as point estimates and 95% confidence intervals. These were not adjusted for multiple testing. These should not be used in place of hypothesis testing or to infer definitive treatment effects.\u003c\/p\u003e\n\n\u003cp\u003eAnalyses of the primary end point and the key secondary end point of alkaline phosphatase normalization at week 52 were performed in the intention-to-treat population. The analyses used the exact Cochran–Mantel–Haenszel test, stratified according to the randomization factors.\u003c\/p\u003e\n\n\u003cp\u003eFor these two binary end points, a composite strategy of imputation of nonresponse was applied. This applied among patients who had intercurrent events before week 52. Intercurrent events were discontinuation of the trial regimen or use of rescue therapy for primary biliary cholangitis. Some patients did not have intercurrent events and had missing data at week 52. Response data for these patients were imputed with data from the closest nonmissing assessment from the double-blind period. That assessment was before or after the date of the theoretical week 52 visit.\u003c\/p\u003e\n\n\u003cp\u003eThe change from baseline in the WI-NRS score through week 52 and through week 24 in patients with moderate-to-severe pruritus was compared using a mixed model for repeated measures. In this model, a hypothetical strategy was applied. Under this strategy, any outcomes after the occurrence of intercurrent events were considered to be missing data. Intercurrent events were discontinuation of the trial regimen or the use of rescue therapy for pruritus. These outcomes were handled within the model under the assumption that the patient continued the trial regimen. Missing data not related to the occurrence of an intercurrent event were similarly handled under a missing-at-random assumption.\u003c\/p\u003e\n\n\u003ch2 id=\"clinical-implications\"\u003eWhat These Results Mean for Patients\u003c\/h2\u003e\n\n\u003cp\u003eThe ELATIVE trial demonstrated that elafibranor, at a dose of 80 mg once daily, produced significantly greater improvements in relevant biochemical indicators of cholestasis (bile flow problems) than placebo. This was in patients with primary biliary cholangitis who had an inadequate response to ursodeoxycholic acid or unacceptable side effects with ursodeoxycholic acid.\u003c\/p\u003e\n\n\u003cp\u003eSpecifically, more than half of patients taking elafibranor (51%) achieved a biochemical response at week 52, compared with only 4% of patients taking placebo. This is a clinically meaningful difference. Elevated alkaline phosphatase and bilirubin levels are used as prognostic indicators of disease progression. This means they help predict the risk of cirrhosis, need for liver transplantation, and premature death.\u003c\/p\u003e\n\n\u003cp\u003eAdditionally, 15% of patients taking elafibranor achieved normalization of their alkaline phosphatase levels, compared with none in the placebo group. Normalization of alkaline phosphatase is considered an important treatment goal in primary biliary cholangitis.\u003c\/p\u003e\n\n\u003cp\u003eHowever, the trial did not demonstrate that elafibranor significantly reduced itch intensity as measured by the WI-NRS, the primary measure of pruritus. This is an important finding, as pruritus is a common and distressing symptom of primary biliary cholangitis that significantly affects quality of life.\u003c\/p\u003e\n\n\u003cp\u003eIt is worth noting that some other itch-related measures appeared to favor elafibranor over placebo. These measures were the PBC-40 itch domain and the 5-D itch scale. These were secondary end points and were not adjusted for multiple testing. Therefore, these measures should be interpreted with caution.\u003c\/p\u003e\n\n\u003cp\u003eThe safety profile of elafibranor was generally manageable. The most common side effects were gastrointestinal in nature (abdominal pain, diarrhea, nausea, and vomiting), and the majority were mild or moderate in intensity. Similar percentages of patients in both groups experienced serious adverse events or discontinued treatment due to adverse events.\u003c\/p\u003e\n\n\u003ch2 id=\"limitations\"\u003eLimitations of the Study\u003c\/h2\u003e\n\n\u003cp\u003eThe ELATIVE trial has several limitations that patients and clinicians should consider:\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003e\n\u003cstrong\u003eDuration:\u003c\/strong\u003e The primary analysis was conducted at 52 weeks. While this is a standard timeframe for assessing biochemical response in primary biliary cholangitis, longer-term data are needed. Longer-term data are needed to determine whether the biochemical improvements translate into reduced risk of cirrhosis, liver transplantation, and death.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eItch results:\u003c\/strong\u003e The trial did not meet its key secondary end point for reducing itch intensity as measured by the WI-NRS. This means that elafibranor's effect on pruritus remains uncertain.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eSample size:\u003c\/strong\u003e The trial enrolled 161 patients, which is relatively small, though appropriate for a rare disease. Subgroup analyses may have limited statistical power.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003ePopulation:\u003c\/strong\u003e The trial population was predominantly female (96%) and White (91%), which reflects the demographics of primary biliary cholangitis but may limit generalizability to other populations.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eSecondary end points:\u003c\/strong\u003e Other secondary end points were not adjusted for multiple testing and should not be used to infer definitive treatment effects.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eOpen-label extension:\u003c\/strong\u003e Patients could enter an open-label extension period after the double-blind period, which may introduce bias in longer-term analyses.\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003ch2 id=\"recommendations\"\u003eRecommendations and Next Steps\u003c\/h2\u003e\n\n\u003cp\u003eBased on the results of the ELATIVE trial, elafibranor represents a promising new treatment option. Elafibranor is for patients with primary biliary cholangitis who have an inadequate response to or unacceptable side effects with ursodeoxycholic acid.\u003c\/p\u003e\n\n\u003cp\u003ePatients who are considering elafibranor should discuss the following with their healthcare provider:\u003c\/p\u003e\n\n\u003col\u003e\n\u003cli\u003e\n\u003cstrong\u003eEligibility:\u003c\/strong\u003e Elafibranor was studied in patients 18 to 75 years of age with an alkaline phosphatase level at least 1.67 times the upper limit of normal and a total bilirubin level no more than 2 times the upper limit of normal.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eExpected benefits:\u003c\/strong\u003e Approximately half of patients taking elafibranor achieved a biochemical response at 52 weeks, and 15% achieved normalization of alkaline phosphatase levels.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eItch:\u003c\/strong\u003e The trial did not demonstrate a significant reduction in itch intensity as measured by the WI-NRS. Patients whose primary concern is pruritus should discuss this with their provider.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eSide effects:\u003c\/strong\u003e The most common side effects were gastrointestinal (abdominal pain, diarrhea, nausea, and vomiting). Most were mild or moderate.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eMonitoring:\u003c\/strong\u003e Patients taking elafibranor should have regular blood tests to monitor liver function and other parameters.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eLong-term data:\u003c\/strong\u003e Longer-term studies are needed to confirm whether the biochemical improvements seen with elafibranor translate into reduced risk of cirrhosis, liver transplantation, and death.\u003c\/li\u003e\n\u003c\/ol\u003e\n\n\u003cp\u003eThe trial was funded by GENFIT and Ipsen. The ELATIVE trial is registered on ClinicalTrials.gov with the number NCT04526665.\u003c\/p\u003e\n\n\u003c!-- ddn:faq:start --\u003e\n\u003ch2 id=\"ddn-faq\"\u003eFrequently Asked Questions\u003c\/h2\u003e\n\u003ch3\u003eWhat is primary biliary cholangitis (PBC)?\u003c\/h3\u003e\n\u003cp\u003ePBC is a rare, chronic liver disease where the immune system attacks the small bile ducts inside the liver. This leads to bile buildup (cholestasis) and eventually liver scarring. It occurs mostly in women aged 40 and older. Without treatment, it can progress to cirrhosis, need for liver transplant, and premature death.\u003c\/p\u003e\n\u003ch3\u003eWhat is elafibranor and how does it work?\u003c\/h3\u003e\n\u003cp\u003eElafibranor is an oral medication that activates two receptor proteins, PPAR-alpha and PPAR-delta. This adjusts the activity of certain genes, which decreases the toxic effects of bile acids and reduces liver inflammation. It is being studied for patients with primary biliary cholangitis who do not respond adequately to or cannot tolerate ursodeoxycholic acid.\u003c\/p\u003e\n\u003ch3\u003eWho was eligible for the ELATIVE trial of elafibranor?\u003c\/h3\u003e\n\u003cp\u003eThe trial enrolled patients aged 18 to 75 with primary biliary cholangitis who had an inadequate response to or unacceptable side effects from ursodeoxycholic acid. They needed an alkaline phosphatase level at least 1.67 times the upper limit of normal and a total bilirubin level no more than 2 times the upper limit of normal. Patients with certain other liver conditions were excluded.\u003c\/p\u003e\n\u003ch3\u003eDid elafibranor reduce itching (pruritus)?\u003c\/h3\u003e\n\u003cp\u003eThe trial did not show that elafibranor significantly reduced itch intensity as measured by the Worst Itch Numeric Rating Scale (WI-NRS) in patients with moderate-to-severe itching. However, two other itch-related measures—the PBC-40 itch domain and the 5-D itch scale—appeared to favor elafibranor, but these were secondary and not adjusted for multiple testing.\u003c\/p\u003e\n\u003ch3\u003eWhat are the side effects of elafibranor?\u003c\/h3\u003e\n\u003cp\u003eThe most common side effects were gastrointestinal: abdominal pain, diarrhea, nausea, and vomiting. These occurred more often with elafibranor than placebo. Most were mild or moderate. Similar percentages of patients in both groups had serious adverse events or stopped treatment due to side effects. Two patients who received elafibranor died during the clinical trial — one from postoperative complications after a surgical operation for an abdominal hernia repair, and one from biliary sepsis and acute kidney injury in a patient with end-stage liver disease — and neither death was considered related to the treatment.\u003c\/p\u003e\n\u003ch3\u003eWhat does a biochemical response mean for patients?\u003c\/h3\u003e\n\u003cp\u003eA biochemical response means meeting three criteria: alkaline phosphatase below 1.67 times the upper limit of normal, at least a 15% drop in alkaline phosphatase from baseline, and total bilirubin at or below the upper limit of normal. These markers help predict risk of cirrhosis, liver transplant, and premature death. However, longer-term data are needed to confirm that these improvements translate into reduced risk of those outcomes.\u003c\/p\u003e\n\u003ch3\u003eI have primary biliary cholangitis and my doctor says I don't respond well enough to ursodeoxycholic acid — when should I get a second opinion about starting elafibranor?\u003c\/h3\u003e\n\u003cp\u003eA second opinion is reasonable when your alkaline phosphatase remains at least 1.67 times the upper limit of normal and your bilirubin stays no more than 2 times the upper limit of normal despite ursodeoxycholic acid treatment, since that is the group studied. In the ELATIVE trial, 51% of patients taking elafibranor achieved a biochemical response at 52 weeks versus 4% taking placebo, and 15% normalized alkaline phosphatase. Itch intensity did not improve significantly, and gastrointestinal side effects were more common. An independent review can help weigh these trade-offs. Diagnostic Detectives Network provides independent expert second opinions.\u003c\/p\u003e\n\u003c!-- ddn:faq:end --\u003e\n\n\u003ch2 id=\"source\"\u003eSource Information\u003c\/h2\u003e\n\n\u003cp\u003e\u003cstrong\u003eOriginal article title:\u003c\/strong\u003e Efficacy and Safety of Elafibranor in Primary Biliary Cholangitis NEJM 2023\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eAuthors:\u003c\/strong\u003e K.V. Kowdley, C.L. Bowlus, C. Levy, U.S. Akarca, M.R. Alvares-da-Silva, P. Andreone, M. Arrese, C. Corpechot, S.M. Francque, M.A. Heneghan, P. Invernizzi, D. Jones, F.C. Kruger, E. Lawitz, M.J. Mayo, M.L. Shiffman, M.G. Swain, J.M. Valera, V. Vargas, J.M. Vierling, A. Villamil, C. Addy, J. Dietrich, J.-M. Germain, S. Mazain, D. Rafailovic, B. Taddé, B. Miller, J. Shu, C.O. Zein, and J.M. Schattenberg, for the ELATIVE Study Investigators' Group\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003ePublication:\u003c\/strong\u003e The New England Journal of Medicine, 2024;390:795-805\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eDOI:\u003c\/strong\u003e 10.1056\/NEJMoa2306185\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003ePublished online:\u003c\/strong\u003e November 13, 2023\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c\/strong\u003e GENFIT and Ipsen\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eClinicalTrials.gov number:\u003c\/strong\u003e NCT04526665\u003c\/p\u003e\n\n\u003cp\u003e\u003cem\u003eThis patient-friendly article is based on peer-reviewed research.\u003c\/em\u003e\u003c\/p\u003e","brand":"DiagnosticDetectives.Com","offers":[{"title":"Default Title","offer_id":47919011528860,"sku":null,"price":0.0,"currency_code":"USD","in_stock":true}],"thumbnail_url":"\/\/cdn.shopify.com\/s\/files\/1\/0599\/5449\/5644\/files\/ddn-medical-article-elafibranor-for-primary-biliary-cholangitis-a-comprehensive-review-of-the-elative-phase-3-trial-hero.png?v=1793341285","url":"https:\/\/diagnosticdetectives.com\/sv\/products\/elafibranor-for-primary-biliary-cholangitis-a-comprehensive-review-of-the-elative-phase-3-trial","provider":"DiagnosticDetectives.Com","version":"1.0","type":"link"}