Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12617001561370
Ethics application status
Approved
Date submitted
26/10/2017
Date registered
16/11/2017
Date last updated
24/08/2018
Type of registration
Retrospectively registered

Titles & IDs
Public title
A Phase 1 Exploratory Placebo and Active-Controlled, Double-Blind, Single and Multiple-Dose Escalation, Pharmacokinetic, Pharmacodynamic and Food Effect Study of CNSA-001 in Healthy Volunteers
Scientific title
A Phase 1 Exploratory Placebo and Active-Controlled, Double-Blind, Single and Multiple-Dose Escalation, Pharmacokinetic, Pharmacodynamic and Food Effect Study of CNSA-001 in Healthy Volunteers
Secondary ID [1] 293208 0
NIL
Universal Trial Number (UTN)
NIL
Trial acronym
NIL
Linked study record
NIL

Health condition
Health condition(s) or problem(s) studied:
Segawa Syndrome 304507 0
Condition category
Condition code
Neurological 303846 303846 0 0
Other neurological disorders
Human Genetics and Inherited Disorders 304613 304613 0 0
Other human genetics and inherited disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Part A:
Subjects in Part A Cohorts 1 through 3 will be randomized to receive single ascending oral doses of CNSA-001, Sapropterin ((6R)-BH4,) or placebo.

Cohort 1 will receive a si ngle 2.5 mg/kg oral dose of CNSA-001 or (6R)-BH4 or Placebo
Cohort 2 will receive a single 7.5 mg/kg oral dose of CNSA-001 or (6R)-BH4 or Placebo
Cohort 3 will receive a single 20 mg/kg) oral dose of CNSA-001 or (6R)-BH4 or Placebo

Subjects in Part A Cohorts 4 and 5 will be randomized to receive single ascending oral doses of CNSA-001 or placebo.

Cohort 4 will receive a single oral dose of CNSA-001 (60 mg/kg) or Placebo
Cohort will receive a single oral dose of CNSA-001 (90 mg/kg) or Placebo

Subjects in Part A Cohort 6 will receive 2 oral doses of CNSA-001 (10 mg /kg) separated by 1 week in a fasted and fed state. Subjects in Cohort 6 of Part A will be fed a standard high-fat (approximately 50 percent of total caloric content of the meal) and high-calorie (approximately 800 to 1000 calories) meal starting 30 minutes prior to receiving their second oral dose of CNSA-001 on Day 8.

Part B:
Subjects in Part B Cohorts 1 through 3 will be randomized to receive multiple oral doses of either CNSA-001 or placebo daily for 7 days at a low, medium, or high oral dose level.

Cohort 1 will receive a multiple oral doses of CNSA-001 (5 mg/kg) or Placebo
Cohort 2 will receive a multiple oral doses of CNSA-001 (20 mg/kg) or Placebo
Cohort 3 will receive a multiple oral doses of CNSA-001 (60 mg/kg) or Placebo
Intervention code [1] 298981 0
Treatment: Drugs
Comparator / control treatment
Placebo (Medisca® Oral Mix – which is commercially available, with microcrystalline cellulose, colloidal silicon dioxide, croscarmellose, ascorbic acid and colorant)
Saproptern ((6R)-BH4) 100 mg tablets

Part A:
Subjects in Part A Cohorts 1 through 3 will receive a single oral dose of CNSA-001, or (6R)-BH4, or placebo,

Subjects in Part A Cohorts 4 and 5 will receive a single oral dose of CNSA-001 or placebo,

Part B:
Subjects in each of the 3 cohorts will receive once oral daily doses of CNSA-001 or placebo for 7 days.

Based on the outcome of the food effect evaluation in Part A, doses in Part B will be administered in either a fasted or a fed state.
Control group
Placebo

Outcomes
Primary outcome [1] 303206 0
The primary objective of Part A is to evaluate the safety and tolerability of single escalating doses of CNSA-001 administered orally to healthy subjects.

Safety will be measured by routine clinical and laboratory procedures, physical examination, collection of vital signs, and recording of AEs and SAEs.

Consistent with first in human clinical trials, sentinel dosing of Cohort 1 will be conducted.

Dose Escalation Safety Reviews - The safety of study subjects will be monitored by the Investigator. After completion of each dose level, the Principal Investigator of the study, a representative of the Sponsor, and the Sponsor’s medical monitor will review the safety data together and approve or deny escalation to the next higher dose. Each dose escalation will be separated by a minimum of 7 days.

The safety of CNSA-001, measured by assessing the incidence and severity of treatment-emergent adverse events (TEAEs) (AEs that begin after start of study drug) and physical examination findings, results of clinical laboratory tests, and vital sign measurements, will be assessed.
Timepoint [1] 303206 0
Cohorts 1-5, Day 1 Through Day 5;
Cohort 6, Day 1 Through Day 11

Following enrollment into the study and administration of the 1st dose of study drug subjects will undergo vital sign measurements and physical examinations on Days 1 through 3 and at End of Study (EOS), as well as clinical laboratory tests (chemistry, hematology, urinalysis) and 12 lead ECG on Day 3 and EOS. Concomitant medications will be recorded from dosing with study drug through EOS.

If 1 or more CNSA-001-treated subjects in a cohort experience any treatment-emergent SAEs or severe AEs, dose escalation will be postponed to re-evaluate the dose in question. The opinion of the Investigator, Sponsor representative, and Sponsor’s medical monitor will be used in evaluating safety data to determine a DLT.

Adverse events will be assessed from the time of informed consent through EOS.
Primary outcome [2] 303207 0
The primary objective of Part B is to evaluate the safety and tolerability of multiple escalating doses of CNSA-001 administered orally healthy subjects

Following enrollment into the study and administration of the 1st dose of study drug subjects will undergo vital sign measurements and physical examinations on Days 1 through 7 and at End of Study (EOS), as well as clinical laboratory tests (chemistry, hematology, urinalysis) and 12 lead ECG on Day 3 and EOS. Concomitant medications will be recorded from dosing with study drug through EOS.

If 1 or more CNSA-001-treated subjects in a cohort experience any treatment-emergent SAEs or severe AEs during the 7-day dosing period, dose escalation will be postponed to re-evaluate the dose in question. The opinions of the Investigator, Sponsor representative, and Sponsor’s medical monitor will be used in evaluating safety data to determine a DLT.

Adverse events will be assessed from the time of informed consent through EOS.
Timepoint [2] 303207 0
Day 1 Through Day 10
Following enrollment into the study and administration of the 1st dose of study drug subjects will undergo vital sign measurements and physical examinations on Days 1 through 7 and at End of Study (EOS), as well as clinical laboratory tests (chemistry, hematology, urinalysis) and 12 lead ECG on Day 3 and EOS. Concomitant medications will be recorded from dosing with study drug through EOS.

If 1 or more CNSA-001-treated subjects in a cohort experience any treatment-emergent SAEs or severe AEs during the 7-day dosing period, dose escalation will be postponed to re-evaluate the dose in question. The opinions of the Investigator, Sponsor representative, and Sponsor’s medical monitor will be used in evaluating safety data to determine a DLT.

Adverse events will be assessed from the time of informed consent through EOS.
Secondary outcome [1] 338238 0
Part A:
Estimate the pharmacokinetic (PK) profile of CNSA-001 after single, escalating oral doses administered to healthy subjects.

The blood concentrations of the study drugs will be listed and summarized with the number of observations, mean, geometric mean, standard deviation, median, maximum, and coefficient of variation (CV). Figures displaying blood concentrations over time as well as non-compartmental PK parameters for the study drugs will be estimated and summarized: AUC0-inf, AUC0-last, Cmax, Tmax, t1/2, and Ke.
Timepoint [1] 338238 0
For Cohorts 1 through 5, sampling for PK analysis will occur predose on Day 1 (within 30 minutes before dosing) and 0.5 hr, 1 hr, 2 hr, 4 hr , 8 hr, 12 hr, and 24 hr postdose.

For Cohort 6, sampling for PK analysis will occur predose on Days 1 and 8 (within 30 minutes before dosing) and 0.5 hr, 1 hr, 2 hr, 4 hr, 8 hr, 12 hr, and 24 hr after the doses on Days 1 and 8, respectively.
Secondary outcome [2] 338239 0
Part A:
Determine the maximum tolerated dose (MTD) of single oral doses of CNSA-001 administered to healthy subjects.

The decision to escalate to each successive dose level will be based on assessment of safety/tolerability, vital sign, and clinical laboratory data through discharge from the CRU after administration of study drug to the final subject in the dosing cohort.
Timepoint [2] 338239 0
After completion of each cohort, the PI of the study, a representative of the Sponsor, and Sponsor’s medical monitor will review the safety data together and approve or deny escalation to the next higher dose. Dosing in each cohort will be separated by a minimum of 7 days.
Secondary outcome [3] 338240 0
Part A: Compare PK profiles of CNSA-001 to (6R)-BH4 after single oral dose administration in Cohorts 1, 2 and 3.

The blood concentrations of the study drugs will be listed and summarized with the number of observations, mean, geometric mean, standard deviation, median, maximum, and coefficient of variation (CV). Figures displaying blood concentrations over time, as applicable, will also be presented. Non-compartmental PK parameters for study drugs will be estimated and summarized: AUC0-inf, AUC0-last, Cmax, Tmax, t1/2, and Ke.

Within Part A, the parameters of AUC0-inf and Cmax. for BH4 will be compared between treated subjects with the study drugs by calculation of geometric mean (GM) ratios within each cohort (Cohorts 1-3). The GM ratio and the corresponding 90% confidence interval will be calculated.
Timepoint [3] 338240 0
For Part A - Cohorts 1 through 3, sampling for PK analysis will occur predose on Day 1 (within 30 minutes before dosing) and 0.5 hr, 1 hr, 2 hr, 4 hr , 8 hr, 12 hr, and 24 hr postdose.

Secondary outcome [4] 338241 0
Part A: Compare the PK profiles of CNSA-001 (obtained from blood concentrations) after single oral dose administration in fasting and fed state.

The parameters of AUC0-inf and Cmax of the study drug will be compared between the fed and fasted state by calculating GM ratios: (GM fasted)/(GM fed) along with the associated 90% confidence intervals.
Timepoint [4] 338241 0
Cohort 6, Day 1 through Day 2 and Day 8 through Day 9 - Sampling for PK analysis will occur on Days 1 and 8 predose (within 30 minutes before dosing on Day 1 and Day 8) and 0.5 hr, 1 hr, 2 hr, 4 hr, 8 hr, 12 hr, and 24 hr postdose (Day 2 and Day 9)
Secondary outcome [5] 338242 0
Part B:
Estimate the PK profile of CNSA-001 after multiple escalating oral doses administered to healthy subjects. The blood concentrations of the study drug will be listed and summarized with the number of observations, mean, geometric mean, standard deviation, median, maximum, and coefficient of variation (CV). Figures displaying blood concentrations over time, as applicable, will also be presented. Non-compartmental PK parameters the study drug will be estimated and summarized (mean, median, minimum, maximum, SD, and CV) along with graphical presentation of the concentration data vs. time. Geometric means will be calculated for all PK parameters except Tmax:
Timepoint [5] 338242 0
Sampling for PK analysis will occur predose on Days 1 and 7 (within 30 minutes before dosing) and 0.5 hr, 1 hr, 2 hr, 4 hr, 8 hr, 12 hr, and 24 hr after the Day 1 and Day 7 doses, respectively. The PK sample collected 24 hours after the Day 1 dose is collected before the Day 2 dose is administered.
Secondary outcome [6] 338243 0
Part B:
Determine the MTD of multiple oral doses of CNSA-001 administered to healthy subjects.

Enrollment to subsequent cohorts will not begin until AE, clinical laboratory, and vital sign data have been reviewed by the Investigator, the Sponsor representative, and the Sponsor’s medical monitor and safety/tolerability demonstrated in the previous cohorts. Dose escalation will continue until identification of a multiple-dose MTD based on evaluation of DLT criteria described below.

If 1 or more CNSA-001-treated subjects in a cohort experience any treatment-emergent SAEs or severe AEs during the 7-day dosing period, dose escalation will be postponed to re-evaluate the dose in question. The opinions of the Investigator, Sponsor representative, and Sponsor’s medical monitor will be used in evaluating safety data to determine a DLT.
Timepoint [6] 338243 0
Day 1 Through Day 8 - Safety will be measured by routine clinical and laboratory procedures, physical examination, collection of vital signs, and recording of AEs and SAEs from the time of the informed consent is signed through the End of Study visit. During the study confinement and dosing periods, AEs and the key safety parameters will be monitored and assessed on a daily basis from Day -1 through Day 8 / discharge.
Secondary outcome [7] 340333 0
In Part B - To characterize changes in neurotransmitter metabolism following administration of the study drug, Subjects in Part B / Cohort 3 will undergo a lumbar puncture to collect a sample of cerebrospinal fluid (CSF) on both Day 1 and on Day 7.
Timepoint [7] 340333 0
In Part B / Cohort 3 - The cerebrospinal fluid (CSF) will be collected via lumbar puncture on Day1 (before dose) and on Day 7 approximately 30 minutes from time of the maximum observed plasma concentration of the study drug (Tmax) as determined from the Part A PK analysis.

The cerebral spinal fluid (CSF) analysis will be analyzed by a qualified bioanalytical laboratory. Descriptive statistics will be provided to characterize any changes in neurotransmitter metabolism between the Day 1, and Day 7 sample results.

Eligibility
Key inclusion criteria
1. Males or females 18 years old and above and weighing equal to or greater than 55 kg and less than or equal 100 kg
2. Informed consent
3. Females must be either postmenopausal for at least 1 year or surgically sterile (having undergone tubal ligation, hysterectomy, or bilateral oophorectomy) for at least 6 months or, if of childbearing potential and not abstinent, willing to use an effective method of contraception from Screening through 30 days after the last dose of study drug:
-Hormonal contraception (stable dose for 3 months)
-Intrauterine device/Intrauterine Hormone-releasing System
-Barrier contraceptive method (diaphragm, cervical cap, contraceptive sponge, condom)
Females who are abstinent will not be required to use a contraceptive method unless they become sexually active.
4. Males with female partners of childbearing potential must agree to use barrier contraceptive (i.e., condom) and their female partners must use a highly effective method of contraception from Screening through 30 days after the last dose of study drug. Males must also refrain from sperm donations during this time period.
5. Males who are abstinent will not be required to use a contraceptive method unless they become sexually active.
6. Females with a negative pregnancy test at Screening and on Day 1 prior to dosing
7. Creatinine clearance (CrCl) >90 mL/min
8. Willing and able to comply with the protocol
9. Have not used tobacco (e.g., cigarettes, e-cigarettes, cigars, smokeless tobacco) for 2 weeks prior to the Screening visit and willingness to abstain from these products through the completion of the study
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Any significant chronic medical illness, as determined by the Investigator
2. Gastrointestinal disease (such as irritable bowel syndrome, inflammatory bowel disease, chronic gastritis, peptic ulcer disease, etc.) that could affect the absorption of the study drug CNSA-001
3. History of gastric surgery, including Roux-en-Y gastric bypass surgery or an antrectomy with vagotomy, or gastrectomy
4. Inability to tolerate oral medication
5. History of allergies or adverse reactions to BH4 or related compounds or to any excipients in the study drug formulation
6. Any clinically significant medical or psychiatric condition or medical history, that in the opinion of the Investigator or the Medical Monitor, would interfere with the subject’s ability to participate in the study or increase the risk of participation for that subject
7. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) laboratory values greater than 2 times the upper limit of normal (ULN)
8. Gilbert’s Syndrome
9. Any other clinically significant laboratory abnormality at the Screening visit or prior to the administration of the first dose of study drug. In general, each laboratory value from screening and baseline chemistry and hematology panels should fall within the limits of the normal laboratory reference range.
10. Current participation in any other investigational drug study or participation within 30 days prior to Screening
11. History of alcohol or drug abuse within last 6 months prior to screening, current evidence of substance dependence or self-reported alcoholic intake >2 drinks/day
12. A female who is nursing or who is planning to become pregnant
13. QTcF (QT with Fredericia’s correction) equal to 460 msec in males and equal to 480 msec in females (based on the mean of triplicate measurements taken at Screening)
14. Resting heart rate of equal to or less than 40 or equal to or greater than 110 beats per minute (bpm) or resting blood pressure less than 90/40 mmHg or greater than 150/90 mmHg at Screening or prior to the first administration of study drug
15. Any other abnormal vital signs that are considered to be clinically significant by the Investigator
16. Is, in the opinion of the Investigator, unwilling or unable to adhere to the requirements of the study
17. Major surgery within the prior 90 days
18. Currently taking an antifolate including, but not limited to, methotrexate
19. Positive test for HIV, hepatitis B, or hepatitis C

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Copies of the randomization sequence and treatment codes will be kept in the pharmacy at the Clinical Research Unit. Unblinded pharmacy (or other qualified site) personnel will be utilized to prepare the study drug for this trial.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
This is a single center Phase 1 study; the randomization will be computer generated, by cohort, using a validated random generator software.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint/s
Pharmacokinetics / pharmacodynamics
Statistical methods / analysis
The sample size for this study is approximately 83 subjects (59 in Part A and 24 in Part B).

The number of subjects in both Part A and Part B was selected to allow sufficient evaluation of safety/tolerability and PK of various sing-dose regimens to be administered in this study and is consistent with standards of practice for Phase 1 studies.

With 6 subjects receiving CNSA-001 within a dose cohort, the probability of observing at least 1 DLT event occurs at a rate of 25% is 0.82.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
10/11/2017
Date of last participant enrolment
Anticipated
30/04/2018
Actual
11/06/2018
Date of last data collection
Anticipated
31/05/2018
Actual
11/07/2018
Sample size
Target
83
Accrual to date
Final
83
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 9381 0
Nucleus Network - Melbourne
Recruitment postcode(s) [1] 18076 0
3004 - Melbourne

Funding & Sponsors
Funding source category [1] 297373 0
Commercial sector/Industry
Name [1] 297373 0
Censa Pharmaceuticals Australia Pty Ltd
Country [1] 297373 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Censa Pharmaceuticals Australia Pty Ltd
Address
C/-PRIME FG
Level 9 HWT Tower Building
40 City Road
Southbank, VIC 3006
Country
Australia
Secondary sponsor category [1] 296351 0
None
Name [1] 296351 0
Address [1] 296351 0
Country [1] 296351 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298477 0
Alfred Hospital Ethics Committee
Ethics committee address [1] 298477 0
Old Baker Building, Level 1,
55 Commercial Rd, Melbourne VIC 3004
Ethics committee country [1] 298477 0
Australia
Date submitted for ethics approval [1] 298477 0
21/08/2017
Approval date [1] 298477 0
25/10/2017
Ethics approval number [1] 298477 0

Summary
Brief summary
The purpose of this study is to establish the safety and tolerability of orally administered CNSA-001 in healthy subjects follow single and multiple-dose escalation

This Phase 1 study will support dose selection for future studies in patients with Segawa Syndrome
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 77206 0
Dr Jason Lickliter
Address 77206 0
The Nucleus Network
Burnet Tower
AMREP Precinct
89 Commercial Rd
Melbourne VIC 3001
Country 77206 0
Australia
Phone 77206 0
+61 3 9076 8960
Fax 77206 0
Email 77206 0
j.lickliter@nucleusnetwork.com.au
Contact person for public queries
Name 77207 0
Mr Taylor Kilfoil
Address 77207 0
Censa Pharmaceuticals Australia Pty Ltd
Floor 19, HWT Tower
40 City Road
Southbank, VIC, 3006
Country 77207 0
Australia
Phone 77207 0
+61 408 880 403
Fax 77207 0
Email 77207 0
taylorkilfoil@censapharma.com
Contact person for scientific queries
Name 77208 0
Dr Neil Smith
Address 77208 0
Censa Pharmaceuticals Inc.
222 Third Street, Suite #2240
Cambridge, Massachusetts, 02142 USA
Country 77208 0
United States of America
Phone 77208 0
+1 317-443-2706
Fax 77208 0
Email 77208 0
nsmith@censapharma.com

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No Supporting Document Provided



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