than 1 x ULN but less 2 x ULN. Patients were randomised (1:1:1) to receive once daily placebo, OCALIVA 10 mg, or OCALIVA titration (5 mg titrated to 10 mg at 6 months dependent on therapeutic response/tolerability). The majority (93%) of patients received treatment in combination with UDCA and a small number of patients (7%) unable to tolerate UDCA received placebo, OCALIVA (10 mg) or OCALIVA titration (5 mg to 10 mg) as monotherapy. ALP and total bilirubin were assessed as categorical variables in the primary composite endpoint, as well as continuous variables over time.
The study population was predominantly female (91%) and white (94%). The mean age was 56 years, with the majority of patients less than 65 years old. Mean baseline ALP values ranged from 316 U/L to 327 U/L. Mean baseline total bilirubin values ranged from 10 μmol/L to 12 μmol/L across treatment arms, with 92% of patients within normal range.
Treatment with OCALIVA 10 mg or OCALIVA titration (5 mg to 10 mg) resulted in clinically and statistically significant increases (p < 0.0001) relative to placebo in the number of patients achieving the primary composite endpoint at all study time points (see Table 3). Responses occurred as early as 2 weeks and were dose dependent (OCALIVA 5 mg compared with 10 mg at 6 months, p=0.0358).
Table 3. Percentage of PBC patients achieving the primary composite endpointa at month 6 and month 12 with or without UDCAb
OCALIVA
10 mgc
(N = 73)
OCALIVA
Titrationc
(N = 70)
Placebo
(N=73)
Month 6
Responders, n (%)
Corresponding 95% CI
37 (51)
39%, 62%
24 (34)
23%, 45%
5 (7)
1%, 13%
p-valued
<0.0001
<0.0001
NA
Month 12
Responders, n (%)
Corresponding 95% CI
35 (48)
36%, 60%
32 (46)
34%, 58%
7 (10)
4%, 19%
p-valued
<0.0001
<0.0001
NA
Components of primary endpointe
ALP less than 1.67-times ULN, n (%)
40 (55)
33 (47)
12 (16)
Decrease in ALP of at least 15%, n (%)
57 (78)
54 (77)
21 (29)
Total bilirubin less than or equal to 1-times ULNf, n (%)
60 (82)
62 (89)
57 (78)
a Percentage of subjects achieving a response, defined as an ALP less than 1.67-times the ULN, total bilirubin within the normal range, and an ALP decrease of at least 15%. Missing values were considered a non-response. The Fisher's exact test was used to calculate the 95% Confidence Intervals (Cis).
b In the trial there were 16 patients (7%) who were intolerant and did not receive concomitant UDCA: 6 patients (8%) in the OCALIVA 10 mg arm, 5 patients (7%) in the OCALIVA titration arm, and 5 patients (7%) in the placebo arm.
c Patients were randomized (1:1:1) to receive OCALIVA 10 mg once daily for the entire 12 months of the trial, or OCALIVA titration (5 mg once daily for the initial 6 months, with the option to increase to 10 mg once daily for the last 6 months, if the patient was tolerating OCALIVA but had ALP 1.67-times the ULN or greater, and/or total bilirubin above the ULN, or less than 15% ALP reduction) or placebo.
dOCALIVA titration and OCALIVA 10 mg versus placebo. P-values are obtained using the Cochran-Mantel-Haenszel General Association test stratified by intolerance to UDCA and pretreatment ALP greater than 3-times ULN and/or AST greater than 2-times ULN and/or total bilirubin greater than ULN.
e Response rates were calculated based on the observed case analysis (i.e., [n=observed responder]/[N=Intention to Treat (ITT) population]); percentage of patients with Month 12 values are 86%, 91% and 96% for the OCALIVA 10 mg, OCALIVA titr |
