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Trial registered on ANZCTR


Registration number
ACTRN12613000522718
Ethics application status
Approved
Date submitted
1/05/2013
Date registered
10/05/2013
Date last updated
7/11/2018
Date data sharing statement initially provided
7/11/2018
Date results information initially provided
7/11/2018
Type of registration
Retrospectively registered

Titles & IDs
Public title
A Phase I/Ib Study to Investigate the Safety, Tolerability and Pharmacokinetic Profile of DSM265 in Healthy Subjects and to Assess the Antimalarial Activity of DSM265 in Healthy Subjects with an Induced Blood Stage Plasmodium falciparum Infection.

PART 1.
Scientific title
A Phase I/Ib Study to Investigate the Safety, Tolerability and Pharmacokinetic Profile of DSM265 in Healthy Subjects and to Assess the Antimalarial Activity of DSM265 in Healthy Subjects with an Induced Blood Stage Plasmodium falciparum Infection.

PART 1.
Secondary ID [1] 282392 0
Registration ID for Part 2 of this study: ACTRN12613000527763
Secondary ID [2] 282503 0
Registration ID for Part 3 of this study: ACTRN12613000533796
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Malaria 288973 0
Condition category
Condition code
Infection 289311 289311 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is essentially a single centre, double-blind, randomised, placebo-controlled, ascending dose study in healthy subjects.

This study is divided into three parts.

The first part comprises of single dose cohorts to assess safety, pharmacokinetics, and the maximum tolerated dose, was well as an assessment of the food effect of DSM265.

The first single ascending dose (SAD) Part 1 of the study will involve up to seven cohorts for the single dose treatment (8 subjects per cohort for cohorts 1 - 6. 10 subjects for Cohort 4 and where the same 10 subjects will be used for Cohort 7. There will be at least a 7 day wash-out period between doses for cohorts 4 and 7.

The mode of administration is an oral solution. As this part is an ascending dose study, the actual dose for the subsequent cohorts will be determined after review of safety and PK data from the first 3 cohorts.
Cohort 1: 6 subjects will receive 25 mg DSM265; 2 subjects placebo;
Cohort 2: 6 subjects will receive 75 mg DSM265; 2 subjects placebo;
Cohort 3: 6 subjects will receive 150 mg DSM265; 2 subjects placebo;
Cohorts 4 (fasted state) and 7 (fed state): 8 subjects will receive x mg DSM265; 2 subjects placebo.
Cohort 5: 6 subjects will receive xx mg DSM265; 2 subjects placebo;
Cohort 6: 6 subjects will receive xxx mg DSM265; 2 subjects placebo.
Intervention code [1] 287025 0
Treatment: Drugs
Comparator / control treatment
Part 1 - SAD Cohort : Placebo which will consist of an oral suspension of the vehicle used for preparation of DSM265, consisting of the same suspension, anti-foaming, and flavouring agents .
Control group
Placebo

Outcomes
Primary outcome [1] 289426 0
The purpose of the study is to determine the maximum oral dose of DSM265 that can be tolerated by healthy adults.

This will be determined by the PK results.
Timepoint [1] 289426 0
PK collections at Day 1 Pre-dose, Day 1 0.5, 1, 2, 4, 6, 8, 12 hrs post dose, Days 2, 3, 5, 7, 10, 14, and 21.

Primary outcome [2] 289528 0
To derive the pharmacokinetic properties of DSM265 in humans (including food effect).

This will be determined by the PK results.
Timepoint [2] 289528 0
PK collections at Day 1 Pre-dose, Day 1 0.5, 1, 2, 4, 6, 8, 12 hrs post dose, Days 2, 3, 5, 7, 10, 14, and 21.

Secondary outcome [1] 302450 0
Nil
Timepoint [1] 302450 0
Nil

Eligibility
Key inclusion criteria
1. Written informed consent must be obtained before any assessment is performed.
2. Healthy male and female (of non-childbearing potential) subjects age 18 to 55 years in good health as determined by past medical history, physical examination, vital signs, electrocardiogram, and laboratory tests at screening.
a. Women are considered post-menopausal and not of child bearing potential if they have had at least 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or six months of spontaneous amenorrhea with serum FSH levels at the local laboratory levels for post-menopause; or have had surgical bilateral oophorectomy or bilateral salpingectomy (with or without hysterectomy) at least six months ago. Women on oral contraceptives are to be excluded from the study, also women who have had a tubal ligation.
3. At screening and baseline, vital signs (systolic and diastolic blood pressure and pulse rate) will be assessed in the sitting position after the subject has rested for at least three (3) minutes and again when required after three (3) minutes in the standing position. Investigators can be guided by the following ranges:
a. oral body temperature between 35.0-37.5 degrees celcius
b. systolic blood pressure, 90-140 mm Hg
c. diastolic blood pressure, 50-90 mm Hg
d. pulse rate, 40-90 bpm
4. When blood pressure and pulse are taken after at least 3 minutes standing, there should be no more than a 20 mm Hg drop in systolic or 10 mm Hg drop in diastolic blood pressure and increase in heart rate (>20 bpm) (compared to the sitting results) associated with clinical manifestation of postural hypotension. Any subject exhibiting clinical manifestations of postural hypotension should be excluded.
5. Must have haematology, clinical chemistry and urinalysis results at screening that are within the reference range or, if outside the range, not clinically significant as judged by the investigator and confirmed and agreed by the medical monitor; aspartate aminotransferase (AST), ALT and bilirubin must be within the reference range at screening
6. Subjects must:
a. Weigh at least 50 kg to participate in the study, and must have a body mass index (BMI) within the range of 18-30 kg/m2.
b. Be able to communicate well with the investigator, to understand and comply with the requirements of the study.
7. Good peripheral venous access
Minimum age
18 Years
Maximum age
55 Years
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Known hypersensitivity to any of the study drugs.
2. Use of other investigational drugs at the time of enrolment, or within 30 days or 5 half-lives of enrolment, whichever is longer; or longer if required by local regulations, and for any other limitation of participation in an investigational trial based on local regulations.
3. History of hypersensitivity to any of the study drugs or to drugs of similar chemical classes
4. A history of clinically significant ECG abnormalities, or any of the following ECG abnormalities at Screening or Baseline:
a. PR >210 msec
b. QRS complex >120 msec
c. QTcF >450 msec or shortened QTcF less than 340 msec or a family history of long QT syndrome or sudden death.
d. Second or third degree atrioventricular block.
e. Incomplete, full or intermittent bundle branch block.
f. Abnormal T wave morphology.
5. History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases.
6. Pregnant or nursing (lactating) women.
7. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, including women whose career, lifestyle, or sexual orientation
precludes intercourse with a male partner and women whose partners have been sterilized by vasectomy or other means.
8. Fertile males, defined as all males physiologically capable of conceiving offspring UNLESS the subject agrees to comply with two highly effective contraceptive methods comprising a barrier method (condom) for the entire duration of the study, and twelve weeks following the last study drug administration. Vasectomised males to use a condom for the entire study and 12 weeks following drug administration.
9. Smokers (use of tobacco products in the previous 3 months). Urine cotinine levels will be measured during screening and at each baseline for all subjects. Smokers will be defined as any subject who reports tobacco use and/or who has a urine cotinine greater than or equal to 500 ng/mL. For light smokers (defined as less than 5 cigarettes per day) to pass the cotinine test, smoking should be stopped at least 24 hours prior to reporting to the centre (i.e., Day -2, early morning). Smoking will not be allowed during the study.
10. Use of any prescription drugs, herbal supplements, within four (4) weeks prior to initial dosing, and/or over-the-counter (OTC) medication, dietary supplements (vitamins included) within two (2) weeks prior to initial dosing (note that diazepam interferes with the analysis of DSM265 and should not have been used for 8 weeks prior to initial dosing). If needed, (i.e. an incidental and limited need) paracetamol is acceptable up 4 g/day, but must be documented in the Concomitant medications / Significant non-drug therapies page of the CRF.
11. Intake of grapefruit, grapefruit juice or other products containing grapefruit within 14 days of the first drug administration.
12. Excessive intake of caffeine drinks or energy drinks within 48 hours before admission defined as more than three 8 oz. cups of coffee a day, equivalent to roughly 250 mg of caffeine. Defined as 1 (6oz) cup of coffee; 2 cans of cola; 1 (12oz) cup of tea; 3oz milk chocolate.
13. Consumption of broccoli, caviar, sardines, liver, heart and kidneys and yeast supplements one day prior to dosing and throughout the dosing phase. tomatoes and vegemite to be avoided 3 hours prior to dosing and 3 hours post dose.
14. Donation or loss of 400 mL or more of blood within eight (8) weeks prior to initial dosing, or longer if required by local regulation.
15. Plasma donation (>100 mL) within 60 days prior to first dosing.
16. Haemoglobin levels below 13.0 g/dL (males) or 11.5 g/dL (females) at screening as determined by Full Blood Cell (FBC) counts.
17. Haptoglobin levels outside reference range for study laboratory.
18. Positive direct antiglobulin test (direct Coomb’s test - DAT).
19. ALT and/or AST and/or lactase dehydrogenase (LDH) should be less than or equal to ULN.
20. Liver enzymes other than ALT, AST, LDH elevated greater than or equal to 1.5xULN within two (2) weeks prior to initial dosing.
21. Recent (within the last three [3] years) and/or recurrent history of autonomic dysfunction (e.g., recurrent episodes of fainting, palpitations, etc.).
22. Recent (within the last three [3] years) and/or recurrent history of acute or chronic bronchospastic disease (including asthma and chronic obstructive pulmonary disease, treated or not treated).
23. History of any food allergies.
24. Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of drugs, or which may jeopardize the subject in case of participation in the study. The Investigator should make this determination in consideration of the subject’s medical history and/or clinical or laboratory evidence of any of the following:
i. Inflammatory bowel disease, ulcers, gastrointestinal or rectal bleeding in the last 6 months;
ii. Major gastrointestinal tract surgery such as gastrectomy, gastroenterostomy, or bowel resection;
iii. Pancreatic injury or pancreatitis in the last 6 months;
iv. The Investigator should be guided by the following criteria:
a. Any single parameter may not exceed 1.5 x upper limit of normal (ULN). A single parameter elevated up to and including 1.5 x ULN should be re-checked once more as soon as possible, and in all cases, at least prior to enrolment/randomisation, to rule out lab error.
b. Any elevation of more than one parameter excludes a subject from participation in the study unless otherwise agreed by the medical monitor. Testing may be repeated once more as soon as possible, but in all cases, at least prior to enrolment/randomisation, to rule out lab error.
Re-check results must not be clinically significant in order for subject to qualify and confirmed and agreed by the medical monitor.
25. History or presence of impaired renal function as indicated by clinically significantly abnormal creatinine or urea values, or abnormal urinary constituents (e.g., albuminuria).
26. Evidence of urinary obstruction or difficulty in voiding at screening.
27. History of immunodeficiency diseases, including a positive HIV (ELISA and Western blot) test result.
28. A positive Hepatitis B surface antigen (HBsAg) or Hepatitis C test result.
29. History of drug or alcohol abuse within the 12 months prior to dosing, or evidence of such abuse as indicated by the laboratory assays conducted during screening and/or baseline.

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)
If a subject is deemed eligible for enrolment into the study and will commence dosing period, a randomisation/ treatment number will be assigned.

A sealed enveloped randomization schedule will be provided to the site by the CRO for subjects to be randomized into a treatment sequence prior to the first dosing.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Subjects will be randomised as per the randomisation schedule provided by the CRO, and the randomisation numbers issued by the unblinded pharmacist.

Method of sequence generation used was the simple randomisation within cohorts using a randomisation table created by computer 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
Other
Other design features
This study is an ascending dose study being studied in 3 parts, and depending on the results of the previous parts, the study can then move on to the next part. It uses an adaptive design. If the pharmacokinetic parameters attain levels acceptable to the sponsor and Safety Review Team, the study will proceed to the induced malaria infection study. Likewise, if the pharmacodynamic parameters attain levels acceptable to the sponsor and Safety Review Team (SRT), the study will proceed to the multiple ascending dose (MAD) phase.
Phase
Phase 1
Type of endpoint(s)
Pharmacokinetics / pharmacodynamics
Statistical methods / analysis

Recruitment
Recruitment status
Completed
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)
QLD

Funding & Sponsors
Funding source category [1] 287168 0
Charities/Societies/Foundations
Name [1] 287168 0
Medicines for Malaria Venture
Address [1] 287168 0
Australian centre for vaccine development
300 Herston Road,
Herston,
Brisbane,
QLD,
Australia,
4006
Country [1] 287168 0
Australia
Funding source category [2] 287169 0
Charities/Societies/Foundations
Name [2] 287169 0
Queensland Institute of Medical Research
Address [2] 287169 0
300 Herston Road,
Herston,
Brisbane,
QLD,
Australia,
4006
Country [2] 287169 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
CPR Pharma Services
Address
28 Dalgleish Street,
Thebarton,
Adelaide,
SA,
Australia,
5031
Country
Australia
Secondary sponsor category [1] 285934 0
None
Name [1] 285934 0
Address [1] 285934 0
Country [1] 285934 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 289165 0
Queensland Institute of Medical Research Human Ethics Committee
Ethics committee address [1] 289165 0
The Queensland Institute of Medical Research,
Post Office Royal Brisbane,
QLD,
Australia,
4029
Ethics committee country [1] 289165 0
Australia
Date submitted for ethics approval [1] 289165 0
22/03/2013
Approval date [1] 289165 0
02/04/2013
Ethics approval number [1] 289165 0
P1523

Summary
Brief summary
The purpose of Part 1 of the study is determine if DSM265 is safe, how it makes people feel and how the body absorbs, processes and gets rid of DSM265 (study drug), in single, increasing oral doses of DSM265 in healthy subjects for the treatment of malaria.

This trial is to be conducted under the Australian Therapeutic Goods Administration (TGA) Clinical Trial Notification Scheme (CTN).
Trial website
Trial related presentations / publications
McCarthy JS, Lotharius J, Rückle T, et al. Safety, tolerability, pharmacokinetics, and activity of the novel long-acting antimalarial DSM265: a two-part first-in-human phase 1a/1b randomised study. Lancet Infect Dis 2017; 17: 626–35
Public notes

Contacts
Principal investigator
Name 39534 0
Prof James McCarthy
Address 39534 0
Q-Pharm Pty Limited, Level 5,
300C Herston Road,
Herston,
QLD,
Australia,
4006
Country 39534 0
Australia
Phone 39534 0
+61 7 3845 3796
Fax 39534 0
+61 7 3362 0104
Email 39534 0
J.McCarthy@uq.edu.au
Contact person for public queries
Name 39535 0
Ms Gem Mackenroth
Address 39535 0
Q-Pharm Pty Ltd
Level 5, 300 Herston Road/Level 6, Block 8,
Royal Brisbane and Women's Hospital,
Herston,
QLD,
Australia,
4029
Country 39535 0
Australia
Phone 39535 0
+ 61 7 3845 3629
Fax 39535 0
+61 7 3845 3630
Email 39535 0
G.Mackenroth@qpharm.com.au
Contact person for scientific queries
Name 39536 0
Dr Suzanne Elliot
Address 39536 0
Q-Pharm Pty Ltd
Level 5, 300 Herston Road/Level 6, Block 8,
Royal Brisbane and Women's Hospital,
Herston,
QLD,
Australia,
4029
Country 39536 0
Australia
Phone 39536 0
+61 7 3845 3644
Fax 39536 0
+61 7 3845 3637
Email 39536 0
S.Elliot@qpharm.com.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
No data sharing plan was in place at the time of this study.
What supporting documents are/will be available?
No other documents available
Summary results
Have study results been published in a peer-reviewed journal?
Yes
Journal publication details
Publication date and citation/details [1] 146 0
March 28, 2017
McCarthy JS, Lotharius J, Rückle T, et al. Safety, tolerability, pharmacokinetics, and activity of the novel long-acting antimalarial DSM265: a two-part first-in-human phase 1a/1b randomised study. Lancet Infect Dis 2017; 17: 626–35
Attachments [1] 146 0
Other publications
Have study results been made publicly available in another format?
No
Results – basic reporting
Results – plain English summary