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Trial registered on ANZCTR


Registration number
ACTRN12612000176864
Ethics application status
Approved
Date submitted
31/01/2012
Date registered
8/02/2012
Date last updated
8/02/2012
Type of registration
Retrospectively registered

Titles & IDs
Public title
A Randomized, Double-blind, Placebo-controlled, First-in-human, 3-Part Study of Orally Administered ALS-002158 to Evaluate the Safety, Tolerability and Pharmacokinetics of
Single Ascending Dosing and Food-effect in Healthy Volunteers, and Multiple Ascending Dosing in Subjects with Chronic Hepatitis C Genotype 1 Infection.
Scientific title
A Randomized, Double-blind, Placebo-controlled, First-in-human, 3-Part Study of Orally Administered ALS-002158 to Evaluate the Safety, Tolerability and Pharmacokinetics of
Single Ascending Dosing and Food-effect in Healthy Volunteers, and Multiple Ascending Dosing in Subjects with Chronic Hepatitis C Genotype 1 Infection.
Secondary ID [1] 279817 0
Nil
Universal Trial Number (UTN)
Nil
Trial acronym
CHC
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Chronic Hepatitis C infection 285701 0
Condition category
Condition code
Infection 285884 285884 0 0
Other infectious diseases
Oral and Gastrointestinal 285905 285905 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Part 1: Healthy Volunteers will receive one of 5 single ascending doses (SAD) of ALS-002158 ranging from 50 mg to 750 mg. ALS-002158 or placebo is administered orally via a syringe.
Subjects in Part 1 and subjects in Part 3 will receive standardized diets at scheduled times that do not conflict with study-related procedures.

Prior to each dose of study medication, subjects will fast from food for at least 8 hours overnight until 4 hours post-dose. Except as part of dose administration, water may be consumed freely until 1 hour prior to dosing through 2 hours post-dosing.

Cohort 1: 50mg
Cohort 2: 100mg
Cohort 3: 300mg
Cohort 4: 500mg
Cohort 5: 750mg

Part 2: Eight Healthy Volunteers from Cohort 3 in Part 1 will receive a second single dose ALS-002158 or placebo (with a washout period of at least 7 days) to assess food effects on pharmacokinetics.

Subjects in Part 2, the food effect study phase, will be given a standardized high-fat content meal within 30 minutes of their second dose; the meal will be completed 10 minutes prior to dosing. The meal will consist of the following:
Two eggs fried in butter
Two strips of bacon
Two slices of toast with butter
Four ounces of hash brown potatoes (fried with butter)
Eight ounces (240 mL) of whole milk

Part 3: Subjects with CHC genotype 1 infection will receive one of 3 doses of ALS-002158 (100 mg, 300 mg, or 500 mg) or placebo for 7 days.
Prior to each dose of study medication subjects will fast from food for at least 8 hours overnight until 4 hours post dose. Except as part of dosing water may be consumed freely until 1 hour prior & 2 hours after dosing. Dosing may occur with food depending on the outcome of Part 2, the food effect study.

Subjects may be dosed in a staggered fashion to accommodate post dosing assessments. Dosing should occur at the same time each day +/- 5 minutes
(e.g., subject 1 is dosed at 7:00AM on MAD Days 1 through 7, subject 2 is dosed at 7:05AM on MAD Days 1-7, etc)
Intervention code [1] 284137 0
Prevention
Intervention code [2] 284159 0
Treatment: Drugs
Comparator / control treatment
There is no comparator, however at the end of the study, the Sponsor will provide access to triple therapy (pegylated interferon, ribavirin and telaprevir) for subjects with CHC who have participated in Part 3.

The placebo will consist of the solution vehicle
containing 60% PEG-400 (Polyethylene glycol 400), 20% water for irrigation and 20% vitamin E TPGS (d-alpha tocopheryl polyethylene glycol 1000 succinate).
Control group
Placebo

Outcomes
Primary outcome [1] 286380 0
Primary:
To evaluate the safety and tolerability of single and multiple doses of ALS-002158 administered to Healthy Volunteers and subjects with CHC genotype 1 infection

This will be done through safety and tolerability testing and will be evaluated continuously throughout the study.

Safety evaluation will include Adverse Events and Serious Adverse Events, vital signs, laboratory tests (including hematology, and serum chemistries), ECGs, physical examination, urinalysis, and pregnancy tests.

Clinical laboratory variables, including hematology, serum chemistries, urinalysis, and urine pregnancy testing will be assessed at screening.

Hematology, serum chemistries, and urine pregnancy testing will be evaluated periodically during treatment and follow-up as indicated.

Vital signs, including resting pulse, respiratory rate, blood pressure, and body temperature.

Part 3 will commence when the third dose of Part 1 is found to be generally safe and tolerable based upon review of the blinded safety and available PK data by the PI and the
Sponsor.

Dosing may occur in a fed or fasted state depending on the outcome of Part 2.
Timepoint [1] 286380 0
Screening will be performed -21 days to day -2
Check-in (in-patient) at Day-1
Randomization and Study drug administration will be done on Day 1.
Checkout of hospital is on Day 3
Follow-Up- will be done on Day 8
Secondary outcome [1] 295737 0
Secondary:
To evaluate the pharmacokinetics of single and repeated doses of ALS-002158 (and its metabolites) in plasma and urine
Timepoint [1] 295737 0
Part 1:
Plasma or whole blood sample timepoints will be performed on:
Before dose administration; 0.25 and 0.5 and 1, 2, 3, 4, 6, 8, 12, 24 (Day 2), 36, 48 (Day 3), 72 (Day 4), 96 (Day
5), 120 (Day 6), 144 (Day 7) and 168 hours (Day 8) post dosing.

Urine sample timepoints:-12-0, 0-6, 6-12, 12-24, 24-30, 30-36, 36-48, 48-72 hours post dose

Part 2:
Plasma PK sample times:
a. Dose 1: before dose administration; 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 24 (Day 2), 36, 48 (Day 3,) 72 (Day 4), 96 (Day 5), 120 (Day 6), 144 (Day 7) and 168
hours (Day 8) post dosing.
b. Dose 2: before dose administration; 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12 (Day 9), 24 (Day 10), 36, 48 (Day 11), 72(Day 12), 96 (Day 13), 120 (Day 14), 144 (Day
15) and 168 (Day 16) hours post-dosing.
No urine samples will be collected in this Part 2.

Part 3:
Plasma PK sample times:
a. Day 1: before dose administration; 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, hours post dosing
b. Day 2-6: pre-dose and 3 hours post-dose, daily
c. Day 7: before dose administration; 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36 (on Day 8), 48 (Day 9), 72 (Day 10), 96 (Day 11), 120(Day 12) & 240 hours (Day17) post-dosing and on Day 31
Urine samples:
a. Day 1: :-12-0, 0-6, 6-12, 12-24, 24-30, 30-36, 36-48 hours post-dosing
b. Day 7: -12-0, 0-6, 6-12, 12-24, 24-30, 30-36, 36-48, 48-72 hours post-dosing
c. Days 10, 11, 12, 17 and 31: 0-24 hour collection (24 hours preceding visit)
Secondary outcome [2] 295738 0
To evaluate the effect of food intake on pharmacokinetics of ALS-002158 in Healthy Volunteers
Timepoint [2] 295738 0
Part 2:
Prior to Dose 2, subjects will consume a high fat meal prior to dosing on Day 9

Dose 2: before dose administration; 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12 (Day 9- meal given), 24 (Day 10), 36, 48 (Day 11), 72(Day 12), 96 (Day 13), 120 (Day 14), 144 (Day 15) and 168 (Day 16) hours post-dosing.
Secondary outcome [3] 295739 0
To evaluate the viral resistance profile after 7 daily doses of ALS-002158 in subjects with CHC genotype 1 infection
Timepoint [3] 295739 0
Part 3:Viral resistance profile

Baseline: Day 1
End of Treatment: Day 7
Completion: Day 31 (plus or minus 1 day)
Month 3: Day 84 (plus or minus14 days)
(plus or minus 2 weeks)
Month 6(plus or minus 2 weeks): Day 68 (plus or minus 14 days)

Eligibility
Key inclusion criteria
Subjects must meet all of the following criteria to be included in the study:
1. Subject has provided written consent.
2. In the investigator’s opinion, the subject is able to understand and comply with protocol requirements, instructions, and protocol.
3. Subject is in good health as deemed by the investigator, based on the findings of a medical evaluation including medical history, physical examination, laboratory tests,
and ECG.
4. Creatinine Clearance of greater than 50 mL/min (Cockroft-Gault)
5. Male or female, 18–55 years of age for Healthy Volunteers and 18-65 for subjects with CHC.
6. Body mass index (BMI) 18–32 kg/m2 inclusive, minimum weight 50 kg for Healthy Volunteers and 18-36 kg/m2 for subjects with CHC, minimum weight of 50 kg in both populations.

No more than 25% of patients in any cohort may be enrolled with Body mass Index of equal or greater than 30 kg/m2.

7. A female is eligible to participate in this study if she is of non-childbearing potential defined as pre-menopausal females with a documented tubal ligation, bilateral
oophorectomy or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea and follicle stimulating hormone (FSH) level within the laboratory’s reference range for postmenopausal females
8. If male, subject is surgically sterile or practicing specific forms of birth control) until 30 days after the end of the study.

In addition, CHC subjects enrolled into the MAD Part (Cohort 1,2 and 3) must also meet the following:
criteria:
1. Positive HCV antibody and a positive HCV RNA at screening.
2. Documentation of CHC infection of greater than 6 months duration at screening.
3. CHC genotype 1 infection at screening.
4. HCV RNA viral load greater than 10to the power of 5 and less than or equal to 10 to the power of 8 IU/mL using a sensitive quantitative assay, e.g., COBAS Taqman- 'Registered Trademark"- HCV Test (version 2.0, Roche).
5. Liver biopsy within two years or Fibroscan evaluation within 6 months prior to screening that clearly excludes cirrhosis (Knodell score <3, Metavir score <3, Ishak score <4). Fibroscan liver stiffness score must be <12 kPa.

6. Absence of hepatocellular carcinoma as indicated by an ultrasound scan conducted during screening.
7. No prior treatment for CHC.
8. Absence of history of clinical hepatic decompensation, e.g., variceal bleeding, ascites, hepatic encephalopathy, or active jaundice.
9. Laboratory values including:
prothombin time <1.5 × ULN
platelets >120,000/mm3
albumin >3.5 g/dL, bilirubin <1.5 mg/dL at screening (subjects with documented Gilbert’s disease allowed)
Serum ALT concentration <5 x Upper Limit of Normal
Alpha Fetoprotein concentration = ULN. If AFP is = ULN, absence of a hepatic mass must be demonstrated by ultrasound within the screening period.
Minimum age
18 Years
Maximum age
65 Years
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Subjects will be ineligible for this study if they meet any one of the following criteria:
1. Clinically significant cardiovascular, respiratory, renal, gastrointestinal, hematologic, neurologic, thyroid, or any uncontrolled medical illness or psychiatric disorder.
2. Positive test for HAV IgM, HBsAg, HCV Ab (HV only), or HIV Ab.
3. Abnormal screening laboratory results that are considered clinically significant by the investigator.

Liver function tests must all be within normal ranges for healthy volunteers (subjects with documented Gilbert’s disease allowed).
4. Drug allergy such as, but not limited to, sulfonamides and penicillins, including those experienced in previous trials with experimental drugs.
5. Any condition that, in the opinion of the investigator, would compromise the study or the well-being of the subject or prevent the subject from meeting the study
requirements.
6. Participation in an investigational drug trial or having received an investigational vaccine within 30 days or 5 half-lives (whichever is longer) prior receiving to study medication.
7. Clinically significant blood loss or elective blood donation of significant volume (i.e. >500 mL) within 60 days of first dose of study drug; >1 unit of plasma within 7 days of
first dose of study drug.
8. Clinically significant abnormal electrocardiogram (ECG) findings.
9. Pregnant or breast feeding females.
10. Unwilling to abstain from alcohol for 48 hours prior to the start of dosing until collection of the final PK sample during each dosing period.
11. For healthy volunteers, history regular consumption of >7 units of alcohol for females and >14 units per week for males (one unit is defined as 10 g alcohol) within 6 months
of first dose.
12. For healthy volunteers, history of regular use of tobacco-(i.e. greater than or equal to 20 cigarettes per day) or nicotine-containing products within 3 months of the screening visit. For subjects with CHC genotype 1 infection, history of regular use of tobacco- or nicotine-containing products is allowed.
13. The subject has a positive pre-study drug screen. A minimum list of drugs that will be screened for includes amphetamines, barbiturates, cocaine, opiates, cannabinoids, and benzodiazepines.
14. Use of concomitant medications, including vitamins or herbal and dietary supplements within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study
medication, unless in the opinion of the Investigator and Medical Monitor the medication will not interfere with the study procedures or compromise subject safety.
15. Subjects must not have received any medication known to be an inducer or inhibitor of CYP450 enzymes within 3 weeks prior to clinic check-in. Such medications will continue
to be prohibited until clinic discharge or commencement of CHC treatment.
16. Exposure to more than four new investigational entities within 12 months prior to the first dosing day.
17. Laboratory abnormalities including:
Thyroid Stimulating Hormone (TSH) >ULN
Hematocrit <34 %
White blood cell counts < 3,500/mm3

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
An independent statistician will be appointed to generate the randomization list and the sealed decoding envelopes. This statistician will not perform the study statistical analysis. Using the Biometrics server, the independent statistician will create a secure directory for the randomization list, with sole access to him and the assistants of the unit. The independent statistician will generate the randomization list and integrate this list in a WORD document.

In order to centralize the randomization and to allocate the randomization numbers in chronological order to the centers, once a patient’s eligibility is confirmed by the investigator, a randomization request form will be filled in by the site and addressed to the BIOTRIAL CTM and lead CRA. A scan of the completed randomization request document should be sent by email between 9:00 and 18h00 CET and a minimum of 4 working days before the expected Day 1.

The BIOTRIAL CTM and/or lead CRA will then complete the randomization request form with the next available randomization number and send it back by email to the site. He will also address it to the BIOTRIAL independent statistician.

4. Upon reception, the BIOTRIAL independent statistician will complete the form with the corresponding treatment to be allocated to the subject and send it by email to an un-blinded person at the investigational centre; most likely the local pharmacy.

In the absence of the independent statistician, another person of the unit (not involved in the study) will be granted access to the randomization list.

The contact information (name, address, e-mail) of each person to whom should be addressed the randomization code must be identified for each centre.

Each centre taking part in the study will receive a global set of sealed decoding envelopes permitting, if necessary, to break the code for all possible randomization numbers.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Cohorts are to be comprised of 10 subjects of which 8 will receive active drug and 2 will receive placebo. The randomization will be performed to maintain a ration of 4 active: 1 palcebo in 2 blocks of 5 subjects.

This will be done by the Sponsor and BIOTRIAL.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint(s)
Safety
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment outside Australia
Country [1] 4089 0
New Zealand
State/province [1] 4089 0
Country [2] 4090 0
Romania
State/province [2] 4090 0
Country [3] 4091 0
France
State/province [3] 4091 0
Country [4] 4092 0
Moldova, Republic Of
State/province [4] 4092 0

Funding & Sponsors
Funding source category [1] 284600 0
Commercial sector/Industry
Name [1] 284600 0
Alios BioPharma Inc
Address [1] 284600 0
260 E Grand Avenue
South San Franciso
Calfornia
94080
Country [1] 284600 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
CPR Pharma Services
Address
Suite C, 32 West Thebarton Road
Thebarton
Adelaide
South Australia
5031
Country
Australia
Secondary sponsor category [1] 283519 0
None
Name [1] 283519 0
Address [1] 283519 0
Country [1] 283519 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 286586 0
Northern X Regional Ethics Committee
Ethics committee address [1] 286586 0
c/- Ministry of Health
650 Great South Rd
Penrose
Auckland
1142
Ethics committee country [1] 286586 0
New Zealand
Date submitted for ethics approval [1] 286586 0
01/11/2011
Approval date [1] 286586 0
02/12/2011
Ethics approval number [1] 286586 0
NTX/11/11/105

Summary
Brief summary
This study is to assess the safety and tolerability and how the investigational drug acts in the body. Healthy volunteers are being used for this trial and patients who suffer from Chronic Hepatitis C infection.
There will be one dose given to the healthy volunteers first and then the results from that will determine the dose levels of the Investigational product to be given in the second part of the study to healthy volunteers. They will also test a dose given before eating and after eating a meal.
In the third part of the study, the results from these two parts will determine dosing for patients who suffer from CHC.
Trial website
Trial related presentations / publications
Publications to be provided by Sponsor.
Public notes

Contacts
Principal investigator
Name 33695 0
Address 33695 0
Country 33695 0
Phone 33695 0
Fax 33695 0
Email 33695 0
Contact person for public queries
Name 16942 0
CPR Pharma Services
Address 16942 0
Suite C, 32 West Thebarton Road
Thebarton
Adelaide
South Australia
5031
Country 16942 0
Australia
Phone 16942 0
+61-08-81251900
Fax 16942 0
+61-08-8354 3146
Email 16942 0
info@cprservices.com.au
Contact person for scientific queries
Name 7870 0
Chris Westland
Address 7870 0
Clinical Development
Alios Biopharma
260 E. Grand Ave., 2nd floor
South San Francisco, CA 94080
Country 7870 0
United States of America
Phone 7870 0
+1-(650) 635-5553
Fax 7870 0
+1-(650) 872 0584
Email 7870 0
cwestland@aliosbiopharma.com

No data has been provided for results reporting
Summary results
Not applicable