| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Cirrhotic Hepatitis C Co-infected With Human Immunodeficiency Virus |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10019641 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To compare throughout the study the efficacy of PEG-Intron® monotherapy versus standard supportive care, using the time to the first occurrence of any one of the following clinical events (death, liver decompensation, liver transplant, hepatocellular carcinoma), in the two treatment groups . |
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| E.2.2 | Secondary objectives of the trial |
To compare the two treatment groups at the EOS:
a) & b) The times and incidence to each of the following EOS: Overall mortality, Liver-related mortality, Liver decompensation, Liver transplants, Hepatocellular carcinoma (HCC)
1. To investigate the safety profile of PEG-Intron in comparison with standard supportive care.
2. To assess the effect of PEG-Intron low dose maintenance treatment on HIV infection progression as determined by: a. changes in CD4 cell count levels, b. changes in HIV RNA titers, c. HIV related infections, d. ART regimen changes.
3. Changes in serum ALT and HCV RNA.
4. Changes in Fibro Scan and APRI during the study period.
5. Changes in hepatic venous pressure gradient (HVPG) levels in a subgroup of subjects from the two treatment groups with available data.
6. Changes in proliferative histological indices and fibrotic scores in a subgroup of paired liver biopsies at the beginning and EOS. Liver biopsies will be obtained from the two treatment groups. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
To be eligible for enrollment, subjects must meet the following inclusion criteria:
1) Display the willingness and ability to participate in the study by demonstrating full comprehension of and agreement to comply with all study procedures by signing the written informed consent.
2) ≥18 years but < 70 years, of either sex or any race.
3) Detectable plasma HCV RNA with all genotypes of HCV permitted. Historical PCR and genotype are acceptable for study entry and will be confirmed at screening through the central lab.
4) Previous non-responders or intolerant to any pegylated alpha interferon plus ribavirin (cannot be on therapy for 2 weeks prior to randomization) or subjects unwilling to complete a full course of any combination treatment (pegylated alpha interferon plus ribavirin) are eligible for this study.
5) Cirrhosis of the liver, confirmed by histopathologic findings.
6) Compensated liver disease measured by the Child-Pugh clinical classification with the hepatic encephalopathy measure equal to one and the total score less than or equal to 8.
7) No evidence of HCC on abdominal ultrasound, CT scan, or MRI scan, and a serum AFP <100 ng/mL within 90 days of randomization/study .
8) Endoscopy to determine if evidence of bleeding (prior or present) due to esophageal varices, gastric varices, or portal gastropathy within six months of randomization/study enrollment. (If evidence of prior variceal bleeding, the patient is not eligible for the study).
9) Serologic evidence of HIV infection by HIV antibody or detection of HIV RNA. (Historical HIV RNA is acceptable for study entry and will be confirmed at screening through a central lab).
10) CD4 cell count ≥100 /µL, regardless of HIV RNA load.
11) Platelet number of at least 50000 mm3.
12) Neutrophil count of at least 750 mm3.
13) Hemoglobin of >9.0 g/dL.
14) Any serum ALT/AST liver enzyme level.
15) Serum thyroid stimulating hormone levels within normal limits, regardless of treatment with L thyroxin.
16) HbA1c<8.5%, to demonstrate controlled diabetes, if applicable.
17) Written clearance from an ophthalmologist must be presented for subjects with a history of hypertension or diabetes prior to treatment start.
18) Creatinine clearance >50 mL/min, as assessed by the indirect calculation method (Appendix 5).
19) Demonstrate stable status of HIV infection, in the opinion of the principal investigator, (e.g., subjects who are expected to progress in the first 3 months of the study would not be appropriate for enrollment).
20) On stable antiretroviral therapy (HAART) for at least 8 weeks prior to baseline.
OR
21) Willing to delay initiation of HAART therapy for at least 6 weeks (for subjects who have not been on HAART for at least 8 weeks prior to randomization).
22) Counseled in the appropriate use of birth control while in this study, as confirmed by the principal investigator or a sub-investigator.
23) While abstinence from sexual activity is the only certain method to prevent pregnancy, female subjects of childbearing potential (includes women who are less than two years post-menopausal and women who may become sexually active during the study) must agree to use a medically acceptable barrier method of contraception (or be surgically sterilized prior to screening) while receiving protocol-specified medication and for one month after stopping the medication.
(a) Acceptable methods of contraception include condoms (male and female) with a spermicidal agent, diaphragm or cervical cap with spermicide, medically prescribed IUD, oral or injectable hormonal contraceptive, and surgical sterilization (e.g., hysterectomy or tubal ligation)
(b) Male subjects who are sexually active must be using an acceptable method of contraception (vasectomy, condoms with spermicide). Contraception must be used during the treatment period and for one month after the completion of therapy, including condom use by male subjects with pregnant partners.
24) Confirmation by the principal investigator or a sub-investigator that sexually active male/female subjects are practicing a method of contraception considered acceptable Contraception must be used during the treatment period and for 1 month after the completion of therapy, including condom use by male subjects with pregnant partners. For subjects who take possible teratogenic HAART regimen (e.g., efavirenz) additional counseling should be given in regard to contraception.
25) Free of any clinically significant disease (other than HCV and HIV) that would interfere with study evaluations.
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| E.4 | Principal exclusion criteria |
Any subject will be excluded from entry into the study if they have ANY of the following criteria:
1) Female who is pregnant, intends to become pregnant during the study or within two months after study completion, or is nursing. Male subjects whose partner wants to become pregnant.
2) Using silymarin.
3) Positive test at screening for anti-HAV IgM Ab, HBsAg, anti-HBc IgM Ab, or HBeAg.
4) Any cause of liver disease other than chronic hepatitis C, including—but not limited to:
a) Hemochromatosis
b) Alpha-1 antitrypsin deficiency
c) Wilson's disease
d) Autoimmune hepatitis
e) Alcoholic liver disease
f) Non-alcoholic steatohepatitis (NASH)
g) Drug-related liver disease
5) Suspected or having hypersensitivity to interferon.
6) History of liver decompensation status or other evidence of bleeding from esophageal varices, signs of current bleeding, significant ascites, hepatic encephalopathy, jaundice or other conditions consistent with decompensated liver disease.
7) Present with a lesion suspicious for hepatic malignancy (HCC or metastasis/metastases) on the screening imaging.
8) Any active malignant disease, suspicion, or history of malignant disease within 5 years prior to study enrollment (except for adequately treated basal cell carcinoma).
9) Known coagulation (e.g., hemophilia) or hemoglobin (e.g., thalassemia) diseases that in the opinion of the investigator presents a risk to the patient to participate in the study
10) Organ transplant, except corneal or hair transplant.
11) Any known preexisting medical condition that, in the investigator’s opinion, could interfere with the subject's participation in and completion of the study, such as:
a) Preexisting psychiatric condition, especially moderate to severe depression, or a history of severe psychiatric disorder, such as psychosis, suicidal ideation, or suicide attempts. Severe depression includes the following:
i) Hospitalization for depression
ii) Electroconvulsive therapy for depression, or
iii) Depression causing a prolonged absence from work or significantly altering daily functions.
Subjects with mild depression may be considered for entry into the study provided that a pre-treatment assessment demonstrates that the subject’s emotional status is clinically stable (either on or off drugs), in which case a management plan must be formulated for the subject; this management plan will become a part of the subject 's medical record.
b) Craniocerebral trauma which is not a concussion, or active seizure disorders requiring medication
c) Clinically significant ECG abnormalities and/or cardiovascular dysfunction within six previous months (e.g., angina, congestive heart failure, recent myocardial infarction, or significant arrhythmia)
d) Chronic lung disease (e.g., chronic obstructive lung disease)
e) Poorly controlled diabetes mellitus
f) Immune-mediated disease (e.g., inflammatory bowel disease [Crohn's disease, ulcerative colitis], idiopathic thrombocytopenic purpura, systemic lupus erythematosus, autoimmune hemolytic anemia, scleroderma, severe psoriasis)
g) Clinical gout
12) Active HIV-related opportunistic infection and/or malignancy requiring systemic therapy.
13) Evidence of known severe retinopathy (e.g., CMV retinitis, macular degeneration).
14) Subjects that in the investigator's opinion are non-reliable for the study conduct or therapy drug administration. These subjects may be – but not limited to – illicit drug/alcohol users whether on substitution therapy or not.
15) Subject has not observed the designated washout periods for any of the prohibited medications outlined in Section 6.2.
16) Participating in any other Hepatitis C clinical study. Subjects who chose to participate in other HIV investigational drugs study may do this if the other protocol allows.
17) Subject is part of the staff or a family member of the staff personnel directly involved with this study.
18) Any other condition that in the opinion of the investigator will make the subject unsuitable for enrollment or will interfere with the subject participating in or completing the study.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint is to measure the time to the first occurrence of any one of the clinical end points (death, liver decompensation, liver transplant and HCC) in the two treatment groups.
Secondary endpoints include:
1. To measure time to death and incidence of deaths in the two treatment groups.
2. To measure time to liver related deaths and liver related deaths incidence at the end of the study in the two treatment groups.
3. To measure time to liver decompensation and liver decompensation incidence in the two treatment groups.
4. To measure time to liver transplant and transplant incidence in the two treatment groups.
5. To measure time to HCC and HCC incidences in the two treatment groups.
6. To measure incidence of combined clinical events in the two treatment groups.
7. To measure and compare the incidence of the treatment dose discontinuation rate, study discontinuation rate, and total SAE's in subjects in the two treatment groups. Thus, to determine whether PEG-Intron has any in vivo interaction with HAART.
8. To measure the effect of PEG-Intron on low dose maintenance treatment on HIV disease progression:
a. Incidence of subjects with an increase in HIV RNA >0.5 log while on stable HAART therapy.
b. Incidence of subjects with a > 50 CD4 cells/cc drop, or >50% whichever is bigger.
c. Incidence of subjects and time to progression to AIDS defining events- defined in Appendix 7.
d. Incidence of subjects’ HAART regimen modification and/or discontinuation.
9. To measure changes in biochemical markers (serum ALT and APRI) and HCV RNA during the study period.
10. To measure changes in Fibro Scan during the study period.
11. To measure the changes in hepatic venous pressure gradient (HVPG) levels in a subgroup of subjects from the two treatment groups with the available data.
12. To score, in paired liver biopsies, the Metavir and Ishak - fibrosis score and histological index at the end of the study in the 2 treatment groups.
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | Yes |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| 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) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Standard Supportive Care - defined by local country guidelines |
|
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 90 |
| 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 | Information not present in EudraCT |
| 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
|
| End of trial: when the last subject has completed the last visit (36 months) or when 80 subjects experienced at least 1 endpoint related clinical event, which ever is sooner. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
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