ANZCTR - Registration

Registration number

ACTRN12617001640392

Ethics application status

Approved

Date submitted

4/10/2017

Date registered

18/12/2017

Date last updated

18/12/2017

Type of registration

Retrospectively registered

Titles & IDs

Public title

A Phase 1, Open-Label, Randomised, Two-Way Crossover Study to Assess the Pharmacokinetics, Relative Bioavailability and Food-Effect of a Single Dose of an Immediate Release and Extended Release Formulation of Propagermanium in Healthy Volunteers

Scientific title

A Phase 1, Open-Label, Randomised, Two-Way Crossover Study to Assess the Pharmacokinetics, Relative Bioavailability and Food-Effect of a Single Dose of an Immediate Release and Extended Release Formulation of Propagermanium in Healthy Volunteers

Secondary ID [1]

DMX-200-101

Universal Trial Number (UTN)

U1111-1202-9051

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

proteinuria

chronic kidney disease

Condition category

Condition code

Renal and Urogenital

Kidney disease

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Phase 1 study in healthy volunteers involving 2 Cohorts (Cohort A and Cohort B).
propagermanium:
Extended Release tablets of 120 mg propagermanium (4 x 30 mg tablets) for oral administration. Single dose administration over three treatment periods.
Participants in Cohort A will receive the immediate release (IR) formulation while fasting at Dose 1, the extended release (ER) formulation while fasting at Dose 2, and the ER formulation after a meal at Dose 3. Participants in Cohort B will receive the ER formulation while fasting at Dose 1, the IR formulation while fasting at Dose 2, and the ER formulation after a meal at Dose 3.
Participants will not have a choice as to which cohort they are assigned (randomised) to and the ratio is 1:1 for each cohort. The IP will be administered with 250 mL water.
All participants from both cohorts will receive study drug on Day 1 (Dose 1), Day 8 (Dose 2) and Day 15 (Dose 3), as such there will be a 7 day wash out period between treatments.

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

Active control treatment: Immediate Release (IR) capsules of 120 mg propagermanium (4 x 30 mg capsules) for single oral dose administration.

Control group

Active

Outcomes

Primary outcome [1]

Assessment of PK parameters of propagermanium in plasma.
Plasma PK parameters: Cmax, tmax, tlag, AUC0-last, kel, AUC8, t1/2, CL/F, Vz/F

Timepoint [1]

Plasma PK sampling schedule:
Day 1 – pre-dose (with 15 mins prior), 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12 and 18 hours post dose 1
Day 2 – 24 and 30 hours post dose 1
Day 8 – pre-dose (with 15 mins prior), 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18 hours post dose 2
Day 9 – 24 and 30 hours post dose 2
Day 15 – pre-dose (with 15 mins prior), 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18 hours post dose 3
Day 16 – 24 and 30 hours post dose 3
The allowed time deviation window for blood sample collection is ± 5 minutes for the samples up to 2 hours, and ± 10 minutes at time points up to 30 hours before a deviation is recorded

Primary outcome [2]

Assessment of the excretion of propagermanium in urine.
Urine PK parameters: Ae, FEgermanium, CLr

Timepoint [2]

Urine PK sampling schedule:
Pre-dose (emptying the bladder), then 0-4, 4-8, 8-12, 12-18, 18-24 and 24-30 hours after dosing

Primary outcome [3]

Assessment of the relative bioavailability of extended release propagermanium between
fasting and fed using Frel=(AUCER(fed)/AUCER(fast))

Timepoint [3]

Plasma PK sampling schedule to assess bioavailability:
Day 1 – pre-dose (with 15 mins prior), 2, 3, 4, 5 and 6 hours post dose 1
Day 2 - 24 and 30 hours post dose 1
Day 8 – pre-dose (with 15 mins prior), 2, 3, 4, 5 and 6 hours post dose 2
Day 9 - 24 and 30 hours post dose 2
Day 15 – pre-dose (with 15 mins prior), 2, 3, 4, 5 and 6 hours post dose 3
Day 16 – 24 and 30 hours post dose 3
The allowed time deviation window for blood sample collection is ± 5 minutes for the samples up to 2 hours, and ± 10 minutes at time points up to 30 hours before a deviation is recorded

Secondary outcome [1]

Assessment of safety.

Timepoint [1]

Vital signs - Body temperature, blood pressure, heart rate, and respiratory rate will be evaluated.. Conducted at Screening, admission, baseline, treatment days 1, 2, 8, 9, 15, 16 and EOS (Day 24)

Clinical laboratory tests:
Biochemistry
• Blood Urea Nitrogen (BUN)
• Creatinine (CREAT)
• Total Bilirubin (BILI)
• Urate (URATE)
• Albumin (ALB)
• Alkaline Phosphatase (ALP)
• Creatine Kinase (CK)
• Aspartate Aminotransferase (AST)
• Alanine Aminotransferase (ALT)
• Glucose (GLUC)
• Sodium (SODIUM)
• Potassium (K)
• Calcium (CA)
• Chloride (CL)
• Bicarbonate (BICARB)
• Total Protein (PROT)
• Lactate Dehydrogenase (LDH)
• g-Glutamyl transferase (GGT)
• Phosphate
• Magnesium
• eGFR
Haematology
• Haemoglobin (HGB)
• Haematocrit (HCT)
• Erythrocytes (RBC)
• Platelets (PLAT)
• Leukocytes (WBC) with differential (including Eosinophils (EOS), Neutrophils
(NEUT), Basophils (BASO), Lymphocytes (LYM) and Monocytes (MONO)
• Mean cell volume
Urinalysis:
• pH (PH)
• Specific Gravity (SPGRAV)
• Protein (PROT)
• Glucose (GLUC)
• Occult Blood (OCCBLD)
• Nitrite (NITRITE)
• Leukocytes (WBC)
Conducted at Screening, admission, treatments days 2, 9, 16 and EOS (Day 24)

Physical examination:
Physical examination includes - general appearance, head, ears, eyes, nose,
throat, dentition, thyroid, chest [heart, lungs], abdomen, skin, neurological, extremities, back, neck, musculoskeletal, and lymph nodes.
Conducted at Screening, admission, treatments days 2, 9, 16 and EOS (Day 24)

Adverse events (AEs)
The most frequently reported adverse events for Serocion® (marketed name for propagermanium) include (all occurring in <2% of the 2,015 patients studied):
• Elevated AST – assessed as part of safety labs
• Elevated ALT – assessed as part of safety labs
• Malaise – reported during AE assessment
• Loss of appetite (18 patients) - reported during AE assessment
Conducted at Screening
Admission
Day 1 - 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18 hours post dose
Day 2 - 24 and 30 hours post dose
Day 8 - 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18 hours post dose
Day 9- 24 and 30 hours post dose
Day 15 - 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 18 hours post dose
Day 16- 24 and 30 hours post dose
EOS (day 24)

12-lead electrocardiogram. All ECG tracings and QTc intervals will be reviewed.
Conducted at Screening
Admission
Day 1 - 3 and 5 hours post dose
Day 2 - 30 hours post dose
Day 8 - 3 and 5 hours post dose
Day 9 - 30 hours post dose
Day 15 - 3 and 5 hours post dose
Day 16 - 30 hours post dose
EOS (Day 24)

Secondary outcome [2]

ADDITIONAL PRIMARY OUTCOME - assessment of the relative bioavailability (Frel) of propagermanium between IR and ER formulations using Frel=(AUCER/AUCIR)

Timepoint [2]

Plasma PK sampling schedule to assess bioavailability:
Day 1 – pre-dose (with 15 mins prior), 2, 3, 4, 5 and 6 hours post dose 1
Day 2 - 24 and 30 hours post dose 1
Day 8 – pre-dose (with 15 mins prior), 2, 3, 4, 5 and 6 hours post dose 2
Day 9 - 24 and 30 hours post dose 2
Day 15 – pre-dose (with 15 mins prior), 2, 3, 4, 5 and 6 hours post dose 3
Day 16 – 24 and 30 hours post dose 3
The allowed time deviation window for blood sample collection is ± 5 minutes for the samples up to 2 hours, and ± 10 minutes at time points up to 30 hours before a deviation is recorded

Eligibility

Key inclusion criteria

1. Healthy male and female volunteers aged between 18 to 50 years old, inclusive, with a body mass index (BMI) between 18.0 and 30.0 kg/m2, who are non-smokers or smoking less than 10 cigarettes/day.
2. Female subjects of childbearing potential must agree to practice true abstinence (when this is in line with their preferred and usual lifestyle) or to use 2 methods of highly effective contraception during the study and for 30 days after the last dose of investigational product, and must have a negative pregnancy test at screening and prior to study drug administration.
3. Male subjects and their partners must agree to use two forms of highly effective methods of contraception during the study and for 90 days after study completion, or agree to remain abstinent during the study and for 90 days after study completion.
4. Able and willing to return to the clinic for all study procedures.
5. Able and willing to provide informed consent.

Minimum age

18 Years

Maximum age

50 Years

Sex

Both males and females

Can healthy volunteers participate?

Yes

Key exclusion criteria

1. Pregnant and breast-feeding women.
2. History or presence of cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrinological, haematological, or neurological disorders capable of significantly altering the absorption, metabolism, or elimination of drugs; constituting a risk when taking the study treatment; or interfering with the interpretation of data.
3. Abnormal blood pressure as determined by the Investigator.
4. Symptomatic herpes zoster within 3 months prior to screening.
5. Known history of active or latent tuberculosis (TB) as documented by medical history and examination, chest X-rays (posterior anterior and lateral), or blood testing.
6. Lymphoma, leukaemia, or any malignancy within the past 5 years except for basal cell or squamous epithelial carcinomas of the skin that have been resected with no evidence of metastatic disease for 3 years.
7. Breast cancer within the past 10 years.
8. Alanine transaminase (ALT) >1.5x upper limit of normal (ULN).
9. Bilirubin >1.5xULN (isolated bilirubin >1.5x ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
10. Current or chronic history of liver disease or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones)
11. Use of over-the-counter or prescription medication including herbal medications (with the exception of hormonal contraception for female participants) within 7 days prior to dosing or during the study period (with the exception of paracetamol).
12. Live vaccine(s) within 1 month prior to screening, or plans to receive any vaccine during the study.
13. Presence of hepatitis B surface antigen (HBsAg) at screening or within 3 months prior to
dosing.
14. Positive hepatitis C antibody test result at screening or within 3 months prior to starting study treatment. NOTE: Participants with positive Hepatitis C antibody due to prior resolved
disease can be enrolled if a confirmatory negative Hepatitis C ribonucleic acid (RNA) test is
obtained.
15. Positive human immunodeficiency virus (HIV) antibody test.
16. Participation in any clinical study with an experimental medication or device within 30 days or 5 half-lives (whichever is longer) of enrolment.
17. Alcohol consumption greater than 28 standard drinks per week or substance abuse likely to impact protocol compliance or data quality as assessed by the Principal Investigator.

Study design

Statistical methods / analysis

The sample size for this study is approximately 14 participants. The study is not intended to show statistical differences between treatment groups.
Safety Analysis Set: All participants who receive any amount of study drug (propagermanium).
PK Analysis Set: All participants who receive study drug (propagermanium) and have sufficient PK data for analysis.
PD Analysis Set: All participants who received any amount of study drug (propagermanium) and who have results from baseline and from greater or equal to 1 post-baseline Pharmacodynamic (PD) assessment.
Frequencies and percentages will be presented for the categorical variable and descriptive statistics (arithmetic mean, standard deviation [SD], median, minimum and maximum) will be presented for continuous variables. Summary results will be presented by treatment (i.e., IR vs ER) and by meal status (i.e. fed vs fasted).
Safety and Tolerability:
Adverse events (AEs) will be coded using the most current Medical Dictionary for Regulatory Activities (MedDRA (Registered Trademark) available at CNS. A by-participant AE data listing, including verbatim term, preferred term, system organ class, treatment, severity, and relationship to study drug, will be provided. The number of participants experiencing treatment emergent AEs (TEAE) and number of individual TEAE will be summarized by treatment group/meal status, system organ class and preferred term. TEAEs will also be summarized by severity and by relationship to study drug.
Laboratory evaluations, vital signs assessments and ECG parameters will be listed for each participant and summarized by treatment group/meal status and protocol specified collection time-point. A summary of change from baseline at each protocol specified time-point will also be presented. Individual time course profiles will be presented for participants with clinical laboratory results deemed clinically significant.
Changes in physical examination will be listed for each participant and described in the text of the final report.
Concomitant medications will be listed by participant and coded using the most current World Health Organization (WHO) drug dictionary available at CNS.
Medical history will be listed by participant.
Pharmacokinetics:
Individual propagermanium concentration data will be listed and summarised by treatment group with descriptive statistics sample size [N], arithmetic mean, SD, median, minimum, maximum and geometric mean). Individual and mean propagermanium concentration-time profiles for each treatment group/meal status will also be presented graphically.
Plasma propagermanium parameters will be determined using a non-compartmental analysis (NCA) approach.
The plasma PK parameters time to maximum observed drug concentration (tmax), maximum observed drug concentration (Cmax), lag time (tlag), area under the curve (AUC) from time zero to last measurable concentration (AUC0-last), AUC from time zero to infinity (AUC8), apparent elimination half-life, apparent terminal elimination rate constant (Kel), apparent clearance (CL/F) and apparent volume of distribution at the terminal phase (Vz/F) (where data are sufficient for parameter determination) will be determined.
The urine PK parameters amount excreted (Ae), fraction of dose excreted (FEgermanium) and renal clearance (CLr) will be determined
Pharmacokinetic parameters will be listed for each participant and summarized by treatment group/meal status using descriptive statistics (N, arithmetic mean, SD, coefficient of variation [CV%], median, minimum, maximum, geometric mean and geometric CV%).
Relative bioavailability of propagermanium will be assessed by estimating the 90% confidence interval (CI) for the ratio of ER vs IR geometric means for the PK parameters AUC0-last and AUC8.
Assessment of a potential food effect will be determined by estimating the 90% Confidence Interval (CI) for the ratio of fed verses fasted geometric means for the PK parameters AUC0-last, AUC8, and Cmax conditions.
Exploratory assessment of CCL2 and plasma and urine inflammatory biomarkers will also be conducted. No formal comparison of biomarkers will be conducted between groups or fed-fasting state.
Additional statistical analysis will be performed if deemed appropriate.

The assessment of biomarkers is an exploratory outcome only.

Recruitment

Recruitment status

Active, not recruiting

Date of first participant enrolment

Anticipated

Actual

9/11/2017

Date of last participant enrolment

Anticipated

Actual

24/11/2017

Date of last data collection

Anticipated

10/12/2017

Actual

Sample size

Target

14

Accrual to date

Final

14

Recruitment in Australia

Recruitment state(s)

WA

Recruitment hospital [1]

Linear Clinical Research - Nedlands

Recruitment postcode(s) [1]

6009 - Nedlands

Funding & Sponsors

Funding source category [1]

Commercial sector/Industry

Name [1]

Dimerix Bioscience Pty Ltd

Country [1]

Australia

Primary sponsor type

Commercial sector/Industry

Name

Clinical Network Services Pty Ltd

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Bellberry Human Research Ethics Committee

Ethics committee address [1]

129 Glen Osmond Road
Eastwood SA 5063

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

20/09/2017

Approval date [1]

23/10/2017

Ethics approval number [1]

Summary

Brief summary

This is a single-centre, randomised, open-label, two-way crossover, single dose study with three treatment periods conducted in healthy participants.  The study is designed to compare the PK profiles of a single oral dose of an immediate and extended release formulation of propagermanium, and to identify if there is a food-effect on the extended release formulation.  Participants who meet all inclusion and none of the exclusion criteria will be evaluated throughout the study. In addition to PK assessments, safety and tolerability data will be collected during the course of the study. 
Approximately 14 participants will be enrolled into two cohorts (Cohort A and Cohort B).  Participants in Cohort A will receive the immediate release (IR) formulation while fasting at Dose 1, the extended release (ER) formulation while fasting at Dose 2, and the ER formulation after a meal at Dose 3.  Participants in Cohort B will receive the ER formulation while fasting at Dose 1, the IR formulation while fasting at Dose 2, and the ER formulation after a meal at Dose 3.  No participant will be a member of more than one cohort. 
Participants will be screened from -14 days prior to dose administration.  Participants will be admitted to the unit on Day -1 and will remain confined to the unit for 24 hours post-dose.  On Day 1, participants will receive Dose 1 and will complete procedures as detailed in Table 3.  On Days 7 and 14 participants will return to the unit and will receive Doses 2 and 3 on Days 8 and 15, respectively and will complete procedures as detailed in Table 3.  Participants will return to the clinic on Day 24 for follow-up visits.

Trial website

Public notes

Contacts

Principal investigator

Name

Dr Peter Schrader

Address

C/- Linear Clinical Research
Level 1 B Block, QEII Medical Centre, Hospital Avenue,
Nedlands, Western Australia, 6009, Australia

Country

Australia

Phone

+61 8 6382 5100

Email

pschrader@linear.org.au

Contact person for public queries

Name

Nicola Norton

Address

Linear Clinical Research
Level 1 B Block, QEII Medical Centre, Hospital Avenue,
Nedlands, Western Australia, 6009, Australia

Country

Australia

Phone

+61 8 6382 5116

Email

nnorton@linear.org.au

Contact person for scientific queries

Name

Peter Schrader

Address

Linear Clinical Research
Level 1 B Block, QEII Medical Centre, Hospital Avenue,
Nedlands, Western Australia, 6009, Australia

Country

Australia

Phone

+61 8 6382 5100

Email

pschrader@linear.org.au

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