| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Primary biliary cirrhosis (PBC) is a chronic and slowly progressive cholestatic liver disease of autoimmune etiology characterized by injury of the intrahepatic bile ducts that may eventually lead to liver failure. Affected individuals are usually in their fifth
to seventh decades of life at time of diagnosis, and 90% are women. |
|
| E.1.1.1 | Medical condition in easily understood language |
| PBC is an autoimmune disease of the liver marked by slow progressive destruction of the small bile ducts of the liver, with the intralobular ducts (Canals of Hering) affected early in the disease. |
|
| E.1.1.2 | Therapeutic area | Body processes [G] - Metabolic Phenomena [G03] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10036680 |
| E.1.2 | Term | Primary biliary cirrhosis |
| E.1.2 | System Organ Class | 100000004871 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The primary objective of this study in subjects with primary biliary cirrhosis (PBC) undergoing daily dosing over a 13-week period is:
To evaluate the effect of LUM001 in combination with ursodeoxycholic acid (UDCA) versus UDCA alone on the reduction of pruritus associated with PBC. |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are:
To evaluate the effect of LUM001 in combination with UDCA versus UDCA alone on alkaline phosphatase levels associated with PBC.
To evaluate the effect of LUM001 in combination with UDCA versus UDCA alone on liver enzymes associated with PBC.
To evaluate the safety and tolerability of LUM001 in combination with UDCA during 13 weeks of therapy in patients with PBC.
The exploratory objectives of this study are:
To explore the effect of LUM001 in combination with UDCA versus UDCA alone on other biochemical markers associated with PBC.
To explore the effect of LUM001 in combination with UDCA versus UDCA alone on quality of life using a PBC-specific health related quality of life (PBC-40) instrument.
To explore the effect of LUM001 in combination with UDCA versus UDCA alone on sleep using the Medical Outcomes Study Sleep Scale (MOS-Sleep). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female subjects between the ages of 18-80 years, inclusive.
2. Diagnosis of PBC [consistent with the American Association for the Study of Liver Disease (AASLD, Section 16.3) Practice Guidelines Practice Guidelines; (Lindor, Gershwin, Poupon, Kaplan, Bergasa, & Heathcote, 2009), as demonstrated by the
documented history of at least 2 of the following diagnostic factors:
a. History of elevated alkaline phosphatase (ALP) levels;
b. Presence of anti-mitochondrial antibodies (AMA) with a titer ≥1:40;
c. Liver biopsy consistent with PBC if a biopsy has been performed;
d. For patients who are AMA negative, a liver biopsy diagnostic for PBC.
3. A previous ultrasound (or equivalent imaging modality) of the biliary tree that excludes biliary obstruction and overt malignancy within 12 months of the screening visit.
4. An average daily score > 4.0 on the Adult Itch Reported Outcome (Adult ItchROTM) questionnaire (maximum possible daily score of 10), for each of two consecutive weeks in the screening period using the eDiary.
5. Taking ursodeoxycholic acid (UDCA) for at least 6 months (stable dose for ≥ 3 months) prior to Day 0, or unable to tolerate UDCA (no UDCA for ≥ 3 months prior to Day 0).
6. If using any of the following medications, must be on a stable dose for the period indicated and expected to remain on the same dose and regimen throughout the treatment period:
a. For 30 days prior to screening: rifampin, antihistamines, opiate antagonists;
b. For 90 days prior to screening: selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs).
7. Females of childbearing potential must have a negative serum pregnancy test [β human chorionic gonadotropin (β-hCG)] during screening and negative urine pregnancy test at the baseline visit.
8. Sexually active females must be postmenopausal, surgically sterile, or if premenopausal, be prepared to use an effective method (≤ 1% failure rate) of contraception during the trial. Effective methods of contraception are considered to be:
a. Hormonal (e.g., contraceptive pill, patch, intramuscular implant or injection) provided subject has been on stable therapy for at least 3 months; or
b. Barrier method, i.e., (a) condom (male or female) or (b) diaphragm, with spermicide; or
c. Intrauterine device (IUD); or
d. Vasectomy (partner).
9. Ability to read and understand English or Spanish in order to use the study-related questionnaires.
10. Ability to read the text on the eDiary screen.
11. Must be willing and able to use an eDiary daily for a minimum of 20 weeks.
12. Must digitally accept the licensing agreement in the eDiary software at the outset of the study.
13. Must complete at least 10 eDiary Adult ItchRO reports (AM or PM) during each of two consecutive weeks of the screening period prior to randomization (maximum possible reports = 14 per week).
14. Access to phone for scheduled calls from study site.
15. Must agree to comply with the study protocol and provide written informed consent. |
|
| E.4 | Principal exclusion criteria |
1. History or presence of other concomitant significant liver disease as assessed by the Investigator including:
a. Hepatitis B infection (HBsAg positive);
b. Hepatitis C infection (antibody positive); patients with a positive antibody test will be eligible if there is documented history of negative HCV RNA and not previously treated for HCV;
c. Any other cholestatic liver disease [e.g., primary sclerosing cholangitis (PSC)];
d. Alcoholic liver disease;
e. Proven overlap autoimmune hepatitis;
f. Proven nonalcoholic steatohepatitis (NASH).
2. Presence of advanced clinical complications of PBC or clinically significant hepatic decompensation, including:
a. History of liver transplantation, current placement on a liver transplant list or current Model for End Stage Liver Disease (MELD) score ≥ 15;
b. Hepatic encephalopathy;
c. Hepatorenal syndrome (type I or II) or screening serum creatinine >2.00 mg/dL (177 μmol/L).
3. Total bilirubin > 2 x ULN at screening.
4. ALT or AST > 5 x ULN at screening.
5. History or presence of any other disease or condition known to interfere with the absorption, distribution, metabolism or excretion of drugs, including bile salt metabolism in the intestine [e.g., inflammatory bowel disease, celiac disease or gastric bypass procedures (gastric lap band is acceptable)].
6. Medical conditions that may cause nonhepatic increases in ALP (e.g., Paget’s disease).
7. Known history of human immunodeficiency virus (HIV) infection.
8. The anticipated need for a surgical procedure within 20 weeks from randomization.
9. Any female who is pregnant or lactating or who is planning to become pregnant within 20 weeks of randomization.
10. Cancer within 5 years of screening, except for basal or squamous cell carcinoma of the skin or in situ cervical carcinoma that has been treated with no evidence of recurrence.
11. History of alcohol abuse, or other substance abuse within 1 year prior to screening.
12.Administration of the following medications:
a. For 12 months prior to randomization: rituximab;
b. For 90 days prior to randomization: azathioprine, mercaptopurine,
mycofenolate, hydroxychloroquine, leflunomide, anti-TNF therapies,
tocilizumab;
c. For 60 days prior to randomization: ≥ 7.5 mg prednisone (or equivalent); (topical, inhaled, or short course therapy for intercurrent illness are permitted), bezafibrate/fenofibrate;
d. For 30 days prior to randomization: methotrexate, bile acid resins (such as cholestyramine), colchicine.
13. Receipt of an investigational drug, biologic, or medical device within 30 days prior to screening, or 5 half-lives of the study agent, whichever is longer.
14. History of noncompliance with medical regimens, unreliability, mental instability or incompetence that could compromise the validity of informed consent or lead to noncompliance with the study protocol.
15.Any other conditions or abnormalities which, in the opinion of the Investigator or Medical Monitor, may compromise the safety of the subject, or interfere with the subject participating in or completing the study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint is change from baseline to Week 13 in pruritus as measured by the weekly sum score using the Adult ItchRO instrument. For this instrument, the subject indicates the severity of their itching in the morning and in the evening each day during screening and during the study period for 13 weeks. The
daily score will be assessed as outlined in Section 8.4.1 of the protocol and will have a range from 0-10, with the higher score indicating increasing itch severity. The Adult ItchRO weekly sum score will be the sum of each daily score over a study week, and is thought to provide a
measure of the weekly burden of itch.
For the change from baseline calculation in the Adult ItchRO weekly sum score, baseline is defined as the weekly sum of the daily scores in the week consisting of the 7 days immediately prior to Day 0. The Week 13 Adult ItchRO weekly sum score is defined as the weekly sum of the daily scores of the week consisting of the 7 days immediately prior to the Week 13 visit. Missing data on the daily score will be imputed using the average daily Adult ItchRO score from that week. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints include:
Change from baseline in pruritus as measured by Adult ItchRo weekly sum scores at Weeks 4 and 8.
Change from baseline in pruritis as measured by the AdultItchRO average daily scores at weeks 4, 8 and 13. The average daily score for a 7-day period will be the sum of the daily scores for the 7-day period divided by the number of days the dairy is completed in that 7-day period
Change from baseline in alkaline phosphatase at Weeks 4, 8 and 13.
Change from baseline in 5-D Itch score at Weeks 4, 8 and 13.
Change from baseline in fasting serum bile acid level at Weeks 4, 8 and 13.
Change from baseline in bile acid synthesis [serum 7α-hydroxy-4-cholesten-3-one (7αC4)] at Weeks 4, 8 and 13.
Exploratory efficacy endpoints include:
Pruritus response rates as measured by Adult ItchRO at Weeks 4, 8 and 13.
Change from baseline for other biochemical markers of cholestasis (total and conjugated bilirubin) at Weeks 4, 8, and 13.
Change from baseline for other liver enzymes (ALT, AST) at Weeks 4, 8 and 13.
Change from baseline for lipid biomarkers (total cholesterol, LDL-C) at Weeks 4 and 13.
Change from baseline for PBC-40 at Weeks 4, 8 and 13.
Change from baseline for MOS-Sleep at Weeks 4 and 13.
Patient Impression of Change (PIC) at Week 13.
Patient Global Therapeutic Benefit (PGTB) assessment at Week 13.
In addition, the following exploratory evaluations will be conducted if the results of the primary and secondary analyses illustrate a difference between drug and placebo treated subjects.
Change from baseline for measures of bile acid synthesis (FGF-19 and FGF-21) at Weeks 4 and 13. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Timepoints for evaluation of each secondary and exploratory endpoint are reported in Section E.5.2 |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
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