U.S. patent application number 11/478879 was filed with the patent office on 2006-11-16 for combination therapy for eradicating detectable hcv-rna in patients having chronic hepatitis c infection.
This patent application is currently assigned to Schering Corporation. Invention is credited to Janice K. Albrecht.
Application Number | 20060257365 11/478879 |
Document ID | / |
Family ID | 25470764 |
Filed Date | 2006-11-16 |
United States Patent
Application |
20060257365 |
Kind Code |
A1 |
Albrecht; Janice K. |
November 16, 2006 |
Combination therapy for eradicating detectable HCV-RNA in patients
having chronic hepatitis C infection
Abstract
There is disclosed a method for treating a patient having
chronic hepatitis C infection to eradicate detectable HCV-RNA
involving a combination therapy using a therapeutically effective
amount of ribavirin and a therapeutically effective amount of
interferon-alpha for a time period of from 20 up to 80 weeks.
Inventors: |
Albrecht; Janice K.; (Winter
Park, FL) |
Correspondence
Address: |
SCHERING-PLOUGH CORPORATION;PATENT DEPARTMENT (K-6-1, 1990)
2000 GALLOPING HILL ROAD
KENILWORTH
NJ
07033-0530
US
|
Assignee: |
Schering Corporation
|
Family ID: |
25470764 |
Appl. No.: |
11/478879 |
Filed: |
June 30, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10255442 |
Sep 26, 2002 |
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11478879 |
Jun 30, 2006 |
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09650841 |
Aug 28, 2000 |
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10255442 |
Sep 26, 2002 |
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08938033 |
Sep 21, 1997 |
6172046 |
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09650841 |
Aug 28, 2000 |
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Current U.S.
Class: |
424/85.7 ;
514/43 |
Current CPC
Class: |
A61K 31/7056 20130101;
A61K 38/21 20130101; Y10S 514/894 20130101; A61K 38/212 20130101;
A61K 38/212 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
424/085.7 ;
514/043 |
International
Class: |
A61K 38/21 20060101
A61K038/21; A61K 31/7056 20060101 A61K031/7056 |
Claims
1. A method of treating a patient having chronic hepatitis C
infection having HCV genotype 1 and having a viral load of greater
than 2 million copies/mL of serum HCV-RNA as measured by
HCV-RNA/qPCR comprising administering to the patient a
therapeutically effective combination of ribavirin and
interferon-alpha for a time period of about 40 to about 50 weeks,
wherein the patient has fewer than about 100 copies/mL of serum
HCV-RNA at the end of said period and also has less than about 100
copies/mL of serum HCV-RNA for at least 24 weeks after the end of
said period.
2. The method of claim 1, wherein the amount of ribavirin
administered is from about 400 to about 1200 mg per day.
3. The method of claim 2, wherein the amount of ribavirin
administered is from about 800 to about 1200 mg per day.
4. The method of claim 1, wherein the interferon-alpha administered
is selected from interferon alpha-2a, interferon alpha-2b, a
consensus interferon, a purified interferon alpha product or a
pegylated interferon-alpha.
5. The method of claim 2, wherein the interferon-alpha administered
is selected from interferon alpha-2a, interferon alpha-2b or a
purified interferon alpha product and the amount of the
interferon-alpha administered is from about 2 to about 10 million
international units (IU) per week on a weekly, three times a week
(EW), every other day (QOD) or daily basis.
6. The method of claim 5, wherein the amount of the
interferon-alpha administered is about 3 million IU TIW.
7. The method of claim 6, wherein the interferon-alpha administered
is interferon alpha-2b.
8. The method of claim 2, wherein the interferon-alpha administered
is consensus interferon and the amount of the interferon-alpha
administered is from about 1 to about 20 micrograms per week on a
weekly, three times a week (TIW), every other day (QOD) or daily
basis.
9. The method of claim 2, wherein the interferon-alpha administered
is pegylated interferon alpha-2b and the amount of the
interferon-alpha administered is from about 0.5 to about 2.0
micrograms/kilogram per week on a weekly, three times a week (TIW),
every other day (QOD) or daily basis.
10. The method of claim 2, wherein the interferon-alpha
administered is pegylated interferon alpha-2a and the amount of the
interferon-alpha administered is from about 20 to about 250
micrograms/kilogram per week on a weekly, three times a week (TIW),
every other day (QOD) or daily basis.
11. The method of claim 2, wherein the patient had previously been
treated with interferon-alpha monotherapy.
12. The method of claim 3, wherein the interferon-alpha
administered is selected from interferon alpha-2a, interferon
alpha-2b or a purified interferon alpha product and the amount of
the interferon-alpha administered is from about 2 to about 10
million international units (IU) per week on a weekly, three times
a week (TIW), every other day (QOD) or daily basis.
13. The method of claim 12, wherein the amount of the
interferon-alpha administered is about 3 million IU TIW.
14. The method of claim 13, wherein the interferon-alpha
administered is interferon alpha-2b.
15. The method of claim 3, wherein the interferon-alpha
administered is consensus interferon and the amount of the
interferon-alpha administered is from about 1 to about 20
micrograms per week on a weekly, three times a week (TIW), every
other day (QOD) or daily basis.
16. The method of claim 3, wherein the interferon-alpha
administered is pegylated interferon alpha-2b and the amount of the
interferon-alpha administered is from about 0.5 to about 2.0
micrograms/kilogram per week on a weekly, three times a week (TIW),
every other day (QOD) or daily basis.
17. The method of claim 3, wherein the interferon-alpha
administered is pegylated interferon alpha-2a and the amount of the
interferon-alpha administered is from about 20 to about 250
micrograms/kilogram per week on a weekly, three times a week (TIW),
every other day (QOD) or daily basis.
18. The method of claim 3, wherein the patient had previously been
treated with interferon-alpha monotherapy.
Description
[0001] Chronic infection with hepatitis C virus is an insidious and
slow-progressing disease having a significant impact on the quality
of life. It can eventually result in cirrhosis of the liver,
decompensated liver disease and/or hepatocelluar carcinoma.
[0002] Alpha interferon monotherapy is commonly used to treat
chronic hepatitis C infection. However, this treatment is not
always effective and sometimes results in intolerable side effects
related to the dosage and duration of therapy. Ribavirin has been
proposed as a monotherapy treatment for chronic hepatitis C
infection (Thomas et al. AASLD Abstracts, Hepatology Vol. 20, NO.
4, Pt 2, Number 440, 1994). However, this monotherapy treatment has
usually been found relatively ineffective and has its own
undesirable side effects. Combination therapy of alpha interferon
and ribavirin has been proposed (Lai, et al. Symposium to the 9th
Biennial Scientific Meeting Asian Pacific Association for the Study
of the Liver. 1994). Preliminary results suggest that the
combination therapy may be more effective than either monotherapy.
Hayden F G, Schlepushkin A N. Combined interferon-a2, rimantadine
hydrochloride, and ribavirin inhibition of influenza virus
replication in vitro. Antimicrob Agents Chemother. 1984;25:53-57.
Schvarcz R, Ando Y, S{grave over ( )}nnerborg A, Weiland O.
Combination treatment with interferon alfa-2b and ribavirin for
chronic hepatitis C in patients who have failed to achieve
sustained response to interferon alone: Swedish experience. J
Hepatology. 1995;232 (Suppl 2):17-21. Brouwer J T, Nevens F,
Michielsen P, et al. What options are left when hepatitis C does
not respond to interferon? Placebo-controlled Benelux multicentre
retreatment trial on ribavirin monotherapy versus combination with
interferon. J Hepatol. 1994;212 (Suppl 1):S17. Abstract WP2/08.
Chemello L, Cavalletto L, Bemardinello E, et al. Response to
ribavirin, to interferon and to a combination of both in patients
with chronic hepatitis C and its relation to HCV genotypes. J
Hepatol. 1994;212 (Suppl 1):S12. Abstract GS5/29. However, no one
has described methods using alpha interferon and ribavirin which
eradicate HCV-RNA in any long-term, effective manner.
[0003] There is a definite need for a method for treating chronic
hepatitis C infection with a combination of alpha interferon and
ribavirin which eradicates HCV-RNA in any long-term, effective
manner.
SUMMARY OF THE INVENTION
[0004] The present invention involves a method of treating a
patient having chronic hepatitis C infection to eradicate
detectable HCV-RNA comprising administering a therapeutically
effective amount of ribavirin and a therapeutically effective
amount of interferon-alpha for a time period of 20 to 30 weeks,
such that at least about 30% of the patients having no detectable
HCV-RNA at the end of said 20 to 30 week period also have no
detectable HCV-RNA for at least 24 weeks after the end of said
administration. Preferably, at least about 40% of the patients
having no detectable HCV-RNA at the end of said 20 to 30 week
period also have no detectable HCV-RNA for at least 24 weeks after
the end of said administration.
[0005] In another embodiment the present invention relates to a
method of treating a patient having chronic hepatitis C infection
to eradicate detectable HCV-RNA comprising administering a
therapeutically effective amount of ribavirin and a therapeutically
effective amount of interferon-alpha for a time period of 40 to 50
weeks, such that at least about 40% of the patients having no
detectable HCV-RNA at the end of said 40 to 50 week period also
have no detectable HCV-RNA for at least 24 weeks after the end of
said administration. Preferably, at least about 50% of the patients
having no detectable HCV-RNA at the end of said 40 to 50 week
period also have no detectable HCV-RNA for at least 24 weeks after
the end of said administration.
[0006] Another embodiment of the invention relates to a method of
treating a patient having chronic hepatitis C infection to
eradicate detectable HCV-RNA comprising administering a
therapeutically effective amount of ribavirin and a therapeutically
effective amount of interferon-alpha for a time period of 60 to 80
weeks, such that at least about 50% of the patients having no
detectable HCV-RNA at the end of said 60 to 80 week period also
have no detectable HCV-RNA for at least 24 weeks after the end of
said administration. Preferably, at least about 60% of the patients
having no detectable HCV-RNA at the end of said 60 to 80 week
period also have no detectable HCV-RNA for at least 24 weeks after
the end of said administration.
[0007] One aspect of the invention involves a method of treating a
patient having chronic hepatitis C infection having HCV genotype
other than type 1 and having a viral load of less than or equal to
2 million copies per ml of serum as measured by HCV-RNA
quantitative PCR to eradicate detectable HCV-RNA comprising
administering a therapeutically effective amount of ribavirin and a
therapeutically effective amount of interferon-alpha for a time
period of 20 to 30 weeks, such that at least about 70% of the
patients having no detectable HCV-RNA at the end of said 20 to 30
week period also have no detectable HCV-RNA for at least 24 weeks
after the end of said administration. Preferably, at least about
80% of the patients having no detectable HCV-RNA at the end of said
20 to 30 week period also have no detectable HCV-RNA for at least
24 weeks after the end of said administration.
[0008] Another aspect of the invention relates to a method of
treating a patient having chronic hepatitis C infection having HCV
genotype other than type 1 and having a viral load of greater than
2 million copies as measured by HCV-RNA/qPCR to eradicate
detectable HCV-RNA comprising administering a therapeutically
effective amount of ribavirin and a therapeutically effective
amount of interferon-alpha for a time period of 20 to 30 weeks,
such that at least about 50% of the patients having no detectable
HCV-RNA at the end of said 20 to 30 week period also have no
detectable HCV-RNA for at least 24 weeks after the end of said
administration. Preferably, at least about 60% of the patients
having no detectable HCV-RNA at the end of said 20 to 30 week
period also have no detectable HCV-RNA for at least 24 weeks after
the end of said administration.
[0009] Yet another aspect of the invention involves a method of
treating a patient having chronic hepatitis C infection having HCV
genotype type 1 and having a viral load of less than or equal to 2
million copies as measured by HCV-RNA/qPCR to eradicate detectable
HCV-RNA comprising administering a therapeutically effective amount
of ribavirin and a therapeutically effective amount of
interferon-alpha for a time period of 20 to 30 weeks, such that at
least about 30% of the patients having no detectable HCV-RNA at the
end of said 20 to 30 week period also have no detectable HCV-RNA
for at least 24 weeks after the end of said administration.
Preferably, at least about 40% of the patients having no detectable
HCV-RNA at the end of said 20 to 30 week period also have no
detectable HCV-RNA for at least 24 weeks after the end of said
administration.
[0010] Still another embodiment of the invention relates to a
method of treating a patient having chronic hepatitis C infection
having HCV genotype type 1 and having a viral load of greater than
2 million copies as measured by HCV-RNAqPCR to eradicate detectable
HCV-RNA comprising administering a therapeutically effective amount
of ribavirin and a therapeutically effective amount of
interferon-alpha for a time period of 20 to 30 weeks, such that at
least about 15% of the patients having no detectable HCV-RNA at the
end of said 20 to 30 week period also have no detectable HCV-RNA
for at least 24 weeks after the end of said administration.
Preferably, at least about 20% of the patients having no detectable
HCV-RNA at the end of said 20 to 30 week period also have no
detectable HCV-RNA for at least 24 weeks after the end of said
administration.
[0011] Preferably, the amount of ribavirin administered is from 400
to 1200 mg per day. More preferably, the amount of ribavirin
administered is from 800 to 1200 mg per day.
[0012] The interferon-alpha administered is preferably selected
from interferon alpha-2a, interferon alpha-2b, a consensus
interferon, a purified interferon alpha product or a pegylated
interferon-alpha. More preferably, the interferon-alpha is selected
from interferon alpha-2a, interferon alpha-2b, or a purified
interferon alpha product and the amount of interferon-alpha
administered is from 2 to 10 million IU per week on a weekly, TIW,
QOD or daily basis. In a preferred embodiment, the interferon-alpha
administered is interferon-alpha-2b and the amount of
interferon-alpha is administered 3 million IU TIW.
[0013] Alternatively, the interferon-alpha administered is
consensus interferon and the amount of interferon-alpha
administered is from 1 to 20 micrograms per week on a weekly, TIW,
QOD or daily basis. In another embodiment, the interferon-alpha
administered is a pegylated interferon alpha-2b and the amount of
interferon-alpha administered is from 0.5 to 2.0
micrograms/kilogram per week on a weekly, TIW, QOD or daily basis.
Alternatively, the interferon-alpha administered is a pegylated
interferon alpha-2a and the amount of interferon-alpha administered
is from 20 to 250 micrograms/kilogram per week on a weekly, TIW,
QOD or daily basis.
[0014] The present invention has surprisingly found that, when
compared to interferon-alpha treatment alone or ribavirin alone,
therapy with a combination of a therapeutically effective amount of
ribavirin and a therapeutically effective amount of
interferon-alpha for a time period of at least 20 to 30 weeks
results in ten times more patients having no detectable HCV-RNA in
their serum at least 24 weeks after termination of therapy than by
either monotherapy.
DETAILED DESCRIPTION
[0015] The term "interferon-alpha" as used herein means the family
of highly homologous species-specific proteins that inhibit viral
replication and cellular proliferation and modulate immune
response. Typical suitable alpha interferons include, but are not
limited to, recombinant interferon alpha-2b such as Intron-A
interferon available from Schering Corporation, Kenilworth, N.J.,
recombinant interferon alpha-2a such as Roferon interferon
available from Hoffmann-La Roche, Nutley, N.J., recombinant
interferon alpha-2C such as Berofor alpha 2 interferon available
from Boehringer Ingelheim Pharmaceutical, Inc., Ridgefield, Conn.,
interferon alpha-n1, a purified blend of natural alpha interferons
such as Sumiferon available from Sumitomo, Japan or as Wellferon
interferon alpha-n1 (INS) available from the Glaxo-Wellcome Ltd.,
London, Great Britain, or a consensus alpha interferon such as
those described in U.S. Pat. Nos. 4,897,471 and 4,695,623
(especially Examples 7, 8 or 9 thereof) and the specific product
available from Amgen, Inc., Newbury Park, Calif., or interferon
alpha-n3 a mixture of natural alpha interferons made by Interferon
Sciences and available from the Purdue Frederick Co., Norwalk,
Conn., under the Alferon Tradename. The use of interferon alpha-2a
or alpha 2b is preferred. Since interferon alpha 2b, among all
interferons, has the broadest approval throughout the world for
treating chronic hepatitis C infection, it is most preferred. The
manufacture of interferon alpha 2b is described in U.S. Pat. No.
4,530,901.
[0016] Ribavirin,
1-.beta.-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide, available
from ICN Pharmaceuticals, Inc., Costa Mesa, Calif., is described in
the Merck Index, compound No. 8199, Eleventh Edition. Its
manufacture and formulation is described in U.S. Pat. No.
4,211,771.
[0017] A person suffering from chronic hepatitis C infection may
exhibit one or more of the following signs or symptoms: [0018] (a)
elevated ALT, [0019] (b) positive test for anti-HCV antibodies,
[0020] (c) presence of HCV as demonstrated by a positive test for
HCV-RNA, [0021] (d) clinical stigmata of chronic liver disease,
[0022] (e) hepatocelluar damage.
[0023] To practice the invention, alpha interferon (hereinafter
.alpha.-IFN) and ribavirin are administered to the patient
exhibiting one of more of the above signs or symptoms in amounts
sufficient to eliminate or at least alleviate one or more of the
signs or symptoms. In a preferred embodiment, the combination
therapy of the invention is administered to a patient who has
failed to remain HCV-RNA free after interferon-alpha
monotherapy.
[0024] The ribavirin is administered to the patient in association
with the .alpha.-IFN, that is, the .alpha.-IFN dose is administered
during the same period of time that the patient receives doses of
ribavirin. Most .alpha.-IFN formulations are not effective when
administered orally, so the preferred method of administering the
.alpha.-IFN is parenterally, preferably by subcutaneous, IV, or IM,
injection. The ribavirin may be administered orally in capsule or
tablet form in association with the parenteral administration of
.alpha.-IFN. Of course, other types of administration of both
medicaments, as they become available are contemplated, such as by
nasal spray, transdermally, by suppository, by sustained release
dosage form, etc. Any form of administration will work so long as
the proper dosages are delivered without destroying the active
ingredient.
[0025] Detectable HCV-RNA in the context of the present invention
means that there is less than 100 copies per ml of serum of the
patient as measured by quantitative, multi-cycle reverse
transcriptase PCR methodology. HCV-RNA is preferably measured in
the present invention by the methodology described below. This
methodology is referred to herein as HCV-RNA/qPCR RNA is extracted
from patient serum using a guaninidium
thiocyanate-phenol-chloroform mister followed by ethanol-ammonium
acetate precipitation. The precipitated RNA is centrifuged and the
resulting pellet is dried in a Centrivap console (Labconco, Kansas
City, Mo.). The dry pellet is then resuspended in 30 microliters of
an Rnasin (Promega Corp., Madison, Wis.), dithiothritol, and
diethylpyrocarbonate-treated water mixture. Samples are kept at or
below -20.degree. C. until RNA reverse transcription (RT) and
PCR.
[0026] In order to convert the entire RNA sequence into cDNA in the
RT reaction, random hexadeoxyribonucleotides (Pharmacia Biotech,
Piscataway, N.J.) are used as primers for the first strand cDNA
synthesis. Two aliquots of 3 microliters of resuspended sample is
added to 3 microliters of 100 ng/.mu.l random primers and
denaturated at 70.degree. C., then reverse transcribed at
40.degree. C. for one hour using M-MLV reverse transcriptase (USB,
Cleveland, Ohio) in standard buffer containing 5 mM MgCl.sub.2. The
final RT reaction volume is 26 .mu.l. The PCR is started
immediately following the reverse transcription.
[0027] A modified version of the PCR method is performed using
heat-stable Taq polymerase to amplify the cDNA. Seventy-five
microliters of PCR mix is added to the entire RT reaction volume
(26 .mu.l) to a final MgCl.sub.2 concentration of 1.5 mM in a total
volume of 101 .mu.l. Each 101 .mu.l sample is then split into 50.5
.mu.l, and a layer of mineral oil is placed on top to prevent
evaporation.
[0028] The PCR cycle consists of annealing for 90 sec., extension
for 90 sec., and denaturation for 90 sec., at 55.degree. X,
74.degree. C. and 94.degree. C., respectively. Thermocycling
samples is submitted to a final 74.degree. C. extension for 10
minutes. Four different cycle sets are used. Bu ;loading the sample
in duplicate, and splitting these samples evenly after RT, there
are four tubes from one sample. Each of the four tubes is given a
different cycle number, enhancing sensitivity and accuracy in the
quantitation process. The thermocycling efficiency will be assessed
by satisfactory amplification of known copy number RNA standards
included in each set of 60 tubes. Two primer sets are used for the
amplification, both from the 5' untranslated region of the HCV
genome. Both of these primer sets are highly conserved and detect
all known subtypes of HCV. Primer set 1: upstream 5'-GTG GTC TGC
GGA ACC GGT GAG T-3', downstream 5'-TGC ACG GTC TAC GAG ACC TC-3'
which produced a 190 bp product. Primer set 2: upstream 5'-CTG TGA
GGA ACT ACT GTC TTC-3', downstream 5'-CCC TAT CAG GCA GTA CCA
CM-3'which produced a 256 bp product.
[0029] The amplified cDNA is then electrophorised in 3% agarose gel
and transferred to nylon membrane. The target DNA is detected by
Southern blotting and immunostaining using a nonradioactive
digoxigenin-labeled DNA probe. These procedures are performed using
automated instruments for PCR thermocycling, agarose gel
electrophoresis, vacuum-transfer Southem blot, hybridization, and
immunostaining. Each membrane contains known copy number serially
diluted standards which are used to construct standard curves for
quantitative measurement of the specimen bands. Originally standard
curves are made from carefully diluted HCV-RNA from transcribed
clones. Radioactive incorporation studies, gel electrophoresis, and
OD 260 are performed on the transcripts to determine that they are
of the expected length. After the production of the RNA transcripts
quantitated clone standards "pooled" standards are generated which
better represent the heterogeneous nature of HCV, one would
encounter in natural infection. These pools are made by combining
large amounts of serum or plasma from known infected individuals.
The serum/plasma pools are calibrated with PCR, against the clone
transcripts and then diluted in the known PCR-negative fluids.
Finally, the higher copy number samples of the pools are checked
against the cDNA Quantiplex nucleic acid detection system from
Chiron Inc. (Emeryville, Calif.). These "double quantitated" pools
are aliquoted and saved at -70.degree. C. Dilutions of 5,000,000,
1,000,000, 500,000, 100,000, 10,000, and 1000 copies/ml are used in
each experiment.
[0030] Each Southern blot membrane is scanned into a computer using
an automated scanner/densitometer, at intervals during development
to determine when the standard curve is most linear. The resultant
electronic images are then measured for band area and mean band
density. All of the reading are standardized to integrated band
density and compared to the standard curve to obtain a numerical
value of viral copy number for each band.
[0031] The following clinical protocols were performed:
[0032] Study 1
[0033] Overall Design and Plan of the Study
[0034] This was a prospective, multicenter, randomized,
double-blind, parallel-group. The study compared treatment with
INTRON.RTM. A plus ribavirin to treatment with INTRON.RTM. A plus
placebo for 24 weeks in patients with compensated chronic hepatitis
C who had responded to one or two previous courses of alpha
interferon (INTRON.RTM. A, Roferon.RTM.-A, or Wellferon.RTM.)
therapy (minimum of 3 MU to a maximum of 6 MU QOD or TIW for a
minimum of 20 weeks to a maximum of 18 months) and who had relapsed
after the most recent course of alpha interferon therapy. Eligible
patients had chronic hepatitis C confirmed by positive serum
HCV-RNA, liver biopsy, and laboratory tests.
[0035] Patients were randomized to treatment with either
INTRON.RTM. A plus ribavirin or INTRON.RTM. A plus placebo. The
dose of INTRON.RTM. A was 3 MU SC TIW; the dose of ribavirin was
1000 or 2000 mg PO daily (based on weight) in two divided doses.
Treatment group assignments were made in equal ratios by a Central
Randomization Center. The randomization procedure was designed to
attempt to balance the treatment groups, within and across sites,
with respect to presence or absence of cirrhosis in the
pretreatment liver biopsy, serum HCV-RNA/qPCR level, and HCV
genotype.
[0036] Study treatment was administered for 24 weeks. The total
course of the study was 48 weeks to determine long-term effect of
treatment.
[0037] During treatment and posttreatment follow-up, biochemical
(ALT), virological (HCV-RNA), and histological (liver biopsy)
examinations were used to assess the nature and duration of
response to study treatment. The primary efficacy variable was the
overall response defined as loss of serum HCV-RNA/qPCR (<100
copies/mL) as measured at 24 weeks following the end of therapy
associated with an improvement in posttreatment liver biopsy as
measured by the Knodell Histology Activity index (HAI).
Normalization of ALT was also examined as a secondary efficacy
variable. The safety of the study treatments was assessed by
monitoring selected laboratory parameters and by also recording and
evaluating the occurrence of any adverse events.
[0038] Treatment Regimens
[0039] The study treatment regimens were either: [0040] INTRON.RTM.
A 3 MU SC TIW plus ribavirin 1000 or 1200 mg/day PO in two divided
doses for 24 weeks ; or [0041] INTRON.RTM. A 3 MU SC TIW plus
placebo matching ribavirin PO in two divided doses for 24
weeks.
[0042] Study treatment was administered for 24 weeks. The standard
INTRON.RTM. A (interferon alfa-2b, recombinant) regimen for
hepatitis C was administered as a fixed dose of 3 MU TIW. Each
patient received instructions regarding the preparation and
subcutaneous administration of INTRON.RTM. A. Ribavirin was
administered twice daily, morning and evening. The dose was
determined by the patient's body weight at the Entry visit.
Patients weighing .ltoreq.75 kg received 1000 mg daily as two 200
mg capsules in the morning and three 200 mg capsules in the
evening. Patients weighing >75 kg received 1200 mg daily as
three 200 mg capsules morning and evening.
[0043] The randomization procedure was designed to balance the
groups with respect to the following Baseline characteristics:
[0044] pretreatment liver histology (cirrhosis or no cirrhosis);
[0045] serum HCV-RNA/qPCR status (HCV-RNA/qPCR.ltoreq.2,000,000 or
HCV-RNA/qPCR>2,000,000 copies/mL); and [0046] HCV Genotype (1 or
other). Patients with mixed genotypes (which include Type 1) will
be classified as Type 1 for purposes of balancing.
[0047] Efficacy
[0048] The primary efficacy objective was comparison of the two
treatment groups with respect to-the overall response rate defined
as loss of serum HCV-RNA/qPCR at 24 weeks following the end of
therapy to an undetectable level or to a level <100 copies/mL
associated with an improvement in Post treatment liver biopsy as
defined by the Knodell HAI inflammation score. The following
secondary efficacy Endpoints were also examined:
[0049] The secondary efficacy Endpoints: [0050] proportions of
patients with normalization of ALT at 24 weeks of follow-up; [0051]
proportions of patients with improvement in biopsy (Categories
I+II+III combined scores); [0052] changes from Baseline in the
biopsy scores (Categories I+II+III combined scores); [0053]
response rates at Endpoint of treatment based on HCV-RNA/qPCR;
[0054] proportion of patients with normalization of ALT at Endpoint
of treatment. [0055] response rates at 24 weeks of follow-up based
on HCV-RNA/qPCR.
[0056] Virology: Entry Status and Change from Entry
[0057] Serum HCV-RNA/qPCR testing was performed by a central
laboratory. A positive HCV-RNA assay result was required at
Baseline; only patients positive for HCV-RNA were eligible to
participate. Repeat assays 20 were scheduled at Weeks 4, 12, 24,
and Follow-up Weeks 12 and 24.
[0058] Response was assessed as defined below:
[0059] Responder: [0060] A patient was classified as a responder at
a given time point if HCV-RNA/qPCR 25 was negative (<100 copies
per mL) at that time point.
[0061] SustainedResponder: [0062] A patient was classified as a
sustained responder if the patient was a responder at 24 weeks of
follow-up. 30 Note that patients who do not meet these criteria,
including patients who discontinued before the required
HCV-RNA/qPCR evaluations were obtained, were classified as
non-responders.
[0063] OverallResponder: [0064] Based on both serum HCV-RNA/qPCR
and change in liver histology as evaluated by the Knodell HAI
Inflammation Score. A patient was classified as an overall
responder to treatment if he/she was a sustained responder and
his/her Post treatment Knodell HAI inflammation score (sum of
categories I+II+III ) improved by 2 or more units relative to the
Pretreatment score.
[0065] Liver Histology
[0066] Liver biopsy was required within the six months preceding
patient enrollment and at Follow-up Week 24. Evaluation of the
biopsies was performed by a single pathologist using the Knodell
Histology Activity Score. The central pathologist was blinded with
respect to patient identification, treatment group, and the time
the biopsy was obtained relative to treatment (Pre- or
Posttreatment). Efficacy of study treatments was assessed by
comparing the degree of inflammatory activity observed at Baseline
with that present at Follow-up Week 24.
RESULTS
[0067] One hundred-ninety-five patients were enrolled at 31
international centers and randomized to treatment with either
INTRON.RTM. A plus ribavirin (N=98) or INTRON.RTM. A plus placebo
(N=97). Three patients, two randomized to receive INTRON.RTM. A
plus ribavirin and one randomized to receive INTRON.RTM. A plus
placebo were not treated; thus, the all-treated groups consisted of
192 patients (96 patients each for INTRON.RTM. A plus ribavirin and
INTRON.RTM. A plus placebo). Two of the three patients were not
treated because they did not wish to continue, the third because
the protocol criteria were not met. All discussions of efficacy and
safety in this report are based on data for the all-treated
groups.
[0068] Efficacy
[0069] The objectives of this study were to compare INTRON.RTM. A
plus ribavirin with INTRON.RTM. A plus placebo with respect to the
overall response rate and the virologic response rate (based on
HCV-RNA (qPCR). The primary efficacy variable for the study is the
overall response rate.
[0070] The conclusion from this regarding efficacy are as follows:
[0071] Combining ribavirin with INTRON.RTM. A can dramatically
increase the proportion of patients who eradicate HCV-RNA and have
significant reduction in hepatic inflammation.
[0072] The End of Follow-up overall response rate is a composite of
the loss of serum HCV-RNA(qPCR) and change in liver histology at
end of follow-up (24 weeks following the end of treatment). A
patient was classified as an overall responder if HCV-RNA(PCR) was
negative at the 24 week posttreatment evaluation and the
posttreatment Knodell HAI inflammation score (sum of categories
I+II+III ) had improved by 2 or more units relative to the
pretreatment score. The End of Follow-up virologic response,
histologic response, and overall response rates are summarized in
Tables 1, 2, and 3.
[0073] End of Follow-up HCV-RNA Response: Sustained Loss of HCV-RNA
24 Weeks Following the End of Treatment
[0074] The proportion of patients with eradication of HCV-RNA in
the serum 24 weeks following the end of treatment was tenfold
greater (p<0.001) in the group of patients treated with the
combination of INTRON.RTM. A plus ribavirin compared to those
receiving INTRON.RTM. A monotherapy. Table 1 summarizes the End of
Follow-up patient response as indicated by serum HCV-RNA.
TABLE-US-00001 TABLE 1 End of Follow-up Serum HCV-RNA: Proportion
of Patients with Eradication of HCV-RNA at 24 Weeks Following the
End of Treatment. Number (%) of Patients INTRON .RTM. A INTRON
.RTM. A Patient Response Status plus Ribavirin plus Placebo p value
All Treated 50/96 (52) 5/96 (5) <0.001 95% Confidence Interval
for each treatment: 42%-62% 1%-10% for difference between 4%-58%
treatments: Responders at End of 49/80 (61) 5/41 (12)
Treatment.sup.c
[0075] Pre- and Posttreatment biopsies were available for 81%
(78/96) of the patients treated with INTRON.RTM. A plus ribavirin
and for 77% (74/96) of those patients who received INTRON.RTM. A
plus placebo. Table 2 summarizes the effect of treatment on hepatic
inflammation for patients with both pre- and posttreatment liver
biopsy results. As with the sustained loss of HCV-RNA replication,
the proportion of patients with improvement in liver inflammation
was significantly greater (p<0.001) in patients receiving
combination therapy compared to those receiving INTRON.RTM. A
monotherapy. TABLE-US-00002 TABLE 2 End of Follow-up Liver
Histology: Improvement in Liver Histology 24 Week Following the End
of Treatment Based on the Knodell HAI (I + II + III) Score. Number
(%) of Patients.sup.b INTRON A IINTRON A plus Ribavirin plus
Placebo Patient Status (n = 78) (n = 74) p value.sup.c Improved
Biopsy.sup.d 49 (51) 30 (31) <0.001 a .sup.bPatients with both
pre- and posttreatment biopsy. .sup.cFisher's Exact test.
.sup.dChange from pretreatment to posttreatment in the Knodell
Histological Index (HAI) score (sum of I + II + III) categorized as
a decrease of 2 or more from pretreatment.
[0076] Overall Response
[0077] When the study was designed, it was recognized that because
liver biopsy is an invasive procedure that it would be unlikely
that posttreatment liver biopsies would be obtained for all
patients. Therefore, the protocol and statistical analysis plan
specified that the analysis for overall response would be based on
data for all treated patients and will be estimated by a maximum
likelihood method (MLE) for patients whose overall response status
could not be determined, ie, patients with negative HCV-RNA and
missing (posttreatment) biopsy evaluations. The protocol also
specified that an additional analysis would be performed on
patients with both pretreatment and posttreatment biopsy results
(ie, patients with complete data). The overall response is
summarized in Table 3 based on the following analyses: [0078]
maximum likelihood estimate (MLE); [0079] patients with complete
data (results for both pre- and posttreatment biopsy);
[0080] patients with missing data (either or both HCV/biopsy)
treated as failures. TABLE-US-00003 TABLE 3 Overall Response Rate.
INTRON .RTM. A IINTRON .RTM. A Data Analyzed plus Ribavirin plus
Placebo p value.sup.b Maximum likelihood estimate 43% 5% <0.001
Patients with complete data.sup.c 39/78 (50%) 4/74 (5%) <0.001
Treat missing as failures.sup.d 39/96 (41%) 4/96 (4%) <0.001 a
.sup.bFisher's exact test. .sup.cComplete data = pre- and
posttreatment biopsy results. .sup.dPatients who had either
virology or biopsy data missing or both were counted as
failures.
[0081] As would be anticipated from individual results for effect
of treatment on eradication of HCV-RNA at end of follow-up and
improvement in hepatic inflammation, the overall response rate in
the INTRON.RTM. A plus ribavirin treatment group was significantly
greater (<0.001), with a 10 to 14 fold improvement, than that
observed in the INTRON.RTM. A plus placebo group for all methods of
evaluation.
[0082] Logistic regression analysis was done on all Baseline
demographic variables and disease characteristics. The only
Baseline statistically significant characteristics predictive of
End of Follow-up sustained response were genotype other than 1 and
viral load .ltoreq.2 million.
[0083] For number of viral copies (.ltoreq.9 million, >2
million), the difference was statistically significant in favor of
higher response rates in patients with .ltoreq.2 million copies
(Table 4).
[0084] When genotype and Baseline virus load are combined, a
hierarchy of response is observed. Those patients with genotype
other than 1 and Baseline virus load .ltoreq.2 million copies had
the best End of Follow-up response; those patients with genotype 1
and >2 million copies had the poorest End of Follow-up response.
TABLE-US-00004 TABLE 4 Disease Characteristics vs Sustained
Response: All-Treated Patients. Number (%) of Patients INTRON A
INTRON A plus ribavirin plus Placebo Disease Characteristic.sup.b
(n = 96) (n = 96) HCV-RNA/qPCR .ltoreq.2 million 24/36 (67) 5/29
(17) .gtoreq.2 million 26/60 (43) 0/67 (0) HCV Genotype.sup.c 1
16/53 (30) 2/53 (4) Other 34/43 (79) 3/19 (7) Genotype/Baseline
HCV-RNA/qPCR Other/.ltoreq.2 million copies 15/16 (93) 3/14 (21)
Other/>2 million copies 18/27 (67) 0/29 (0) 1/.ltoreq.2 million
copies 8/20 (40) 0/15 (0) 1/>2 million copies 7/33 (21) 0/38 (0)
a .sup.bAt entry, patients were stratified by number of viral
copies (.ltoreq.2 million, >2 million), genotype (1 or other),
and cirrhosis (present or absent).
[0085] Study 2:
[0086] By basically the same methodology as described above in
Study 1, a second Study 2 was also conducted. The results are
summarized below.
[0087] Efficacy
[0088] The End of Follow-up overall response rate is a composite of
the loss of serum HCV-RNA(qPCR) and change in liver histology at
End of Follow-up (24 weeks following the end of treatment). A
patient was classified as an overall responder if HCV-RNA(PCR) was
negative at the 24 week posttreatment evaluation and the
posttreatment Knodell HAI inflammation score (sum of categories
I+II+III ) had improved by 2 or more units relative to the
pretreatment score. The End of Follow-up virologic response,
histologic response, and overall response rates are summarized in
Tables 5, 6, and 7.
[0089] End of Follow-up HCV-RNA Response: Sustained Loss of HCV-RNA
24 Weeks Following the End of Treatment
[0090] The proportion of patients with eradication of HCV-RNA in
the serum 24 weeks following the end of treatment was ten-fold
(p<0.001), in the group of patients treated with the combination
of INTRON.RTM. A plus ribavirin compared to those receiving
INTRON.RTM. A monotherapy. Table 5 summarizes the End of Follow-up
patient response as indicated by serum HCV-RNA. TABLE-US-00005
TABLE 5 End of Follow-up Serum HCV-RNA: Proportion of Patients with
Eradication of HCV-RNA at 24 Weeks Following the End of Treatment.
Number (%) of Patients INTRON A INTRON A Patient Response Status
plus Ribavirin plus Placebo p value All -treated Patients 34/77
(44) 3/76 (4) <0.001 95% Confidence Interval for each treatment:
33%-56% 0%-8% for difference between 28%-52% treatments Responders
at End of 34/54 (63) 3/32 (9) Treatment.sup.c
[0091] End of Follow-up Liver Histology: Improvement in Liver
Histology 24 Weeks Following the End of Treatment Based on Knodell
Histological Activity Index (HAI) Scores (I+II+III)
[0092] Pre- and Posttreatment biopsies were available for 79%
(61/77) of the patients treated with INTRON.RTM. A plus ribavirin
and for 84% (64/76) of those patients who received INTRON.RTM. A
plus placebo. Table 6 summarizes the effect of treatment on hepatic
inflammation for patients with both pre- and posttreatment liver
biopsy results. As with the sustained loss of HCV-RNA replication,
the proportion of patients with improvement in liver inflammation
was significantly greater (p<0.001) in patients receiving
combination therapy compared to those receiving INTRON.RTM. A
monotherapy. TABLE-US-00006 TABLE 6 End of Follow-up Liver
Histology: Improvement in Liver Histology 24 Weeks Following the
End of Treatment Based on the Knodell HAI (I + II + III) Score.
Number (%) of Patients.sup.b INTRON A INTRON A plus Ribavirin plus
Placebo Patient Status (n = 61) (n = 64) p value.sup.c Improved
Biopsy.sup.d 38 (49) 27 (36) <0.001 a .sup.bPatients with both
pre-and posttreatment biopsy. .sup.cFisher's Exact test.
.sup.dChange from pretreatment to posttreatment in the Knodell
Histological Index (HAI) score (sum of I + II + III) categorized as
a decrease of 2 or more from pretreatment.
[0093] Overall Response
[0094] The overall response is summarized in Table 7 based on the
following analyses: [0095] maximum likelihood estimate (MLE);
[0096] patients with complete data (results for both pre- and
posttreatment biopsy);
[0097] patients with missing data (either or both HCV-RNA/biopsy)
treated as failures. TABLE-US-00007 TABLE 7 Overall Response Rate.
INTRON A INTRON A Data Analyzed plus Ribavirin plus Placebo p
value.sup.b ML Estimate 36.5% 2.7% <0.001 Patients with complete
data.sup.c 25/61 (41.0%) 2/64 (3.1%) <0.001 Treat missing as
failures.sup.d 25/77 (32.5%) 2/76 (2.6%) <0.001 a .sup.bFisher's
Exact test. .sup.cComplete data = pre- and posttreatment biopsy
results. .sup.dPatients who had either virology or biopsy data
missing or both were counted as failures..
[0098] As would be anticipated from individual results for effect
of treatment on eradication of HCV-RNA at End of Follow-up and
improvement in hepatic inflammation, the overall response rate in
the INTRON A plus ribavirin group is significantly greater
(p<0.001) with a 10-14 fold improvement over that observed with
INTRON A plus placebo groups for all methods of evaluation.
[0099] Logistic regression analysis was done on all Baseline
demographic variables and disease characteristics. The only
Baseline statistically significant characteristic predictive of End
of Follow-up sustained response was genotype other than 1.
[0100] For number of viral copies (.ltoreq.2 million, >2
million), there was a numerical difference in favor of higher
response rates in patients with .ltoreq.2 million copies (Table 8).
When genotype and Baseline virus load are combined, a hierarchy of
response is observed. Those patients with genotype other than 1 and
Baseline virus load .ltoreq.2 million copies had the best End of
Follow-up response; those patients with genotype 1 and >2
million copies had the poorest End of Follow-up response.
TABLE-US-00008 TABLE 8 Disease Characteristics vs Sustained
Response: All-Treated Patients. Number (%) of Pataients INTRON
.RTM. A INTRON .RTM. A plus ribavirin plus Placebo Disease
Characteristic (n = 77) (n = 76) HCV-RNA/qPCR .ltoreq.2 million 6/9
(67) 1/12 (8) >2 million 28/68 (41) 2/64 (3) HCV Genotype 1
12/46 (28) 1/42 (2) Other 21/31 (68) 2/34 (6) Genotype/Baseline
HCV-RNA/qPCR Other/.ltoreq.2 million copies 4/4 (100) 0/3 (0)
Other/>2 million copies 17/27 (62) 2/31 (6) 1/.ltoreq.2 million
copies 2/5 (40) 1/9 (11) 1/>2 million copies 11/39 (28) 0/32
(0)
[0101] Many modifications and variations of this invention can be
made without departing from its spirit and scope, as will be
apparent to those skilled in the art. The specific embodiments
described herein are offered by way of example only, and the
invention is to be limited only by the terms of the appended
claims, along with the full scope of equivalents to which such
claims are entitled.
Sequence CWU 1
1
* * * * *