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Trial registered on ANZCTR


Registration number
ACTRN12613000527763
Ethics application status
Approved
Date submitted
6/05/2013
Date registered
13/05/2013
Date last updated
26/04/2017
Type of registration
Prospectively 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 2.
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 2.
Secondary ID [1] 282435 0
Registration ID for Part 1 of the study: ACTRN12613000522718
Secondary ID [2] 282502 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 289041 0
Condition category
Condition code
Infection 289384 289384 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 second part explores the effect of DSM265 on an induced malaria infection study in a single cohort. This part of the study will run as open-label.

There will be 1 cohort of 10 subjects enrolled. All participants will receive a malaria inoculum injection of ~ 1,800 viable P. falciparum infected human erythrocytes. 8 subjects will receive a single dose of the maximum tolerated dose (determined from Part 1) of DSM265 via an oral suspension 7 days after malaria inoculation. 2 subjects will receive Mefloquine tablets (250 mg). The effects of DSM265 will be observed for 16 days before compulsory treatment with Riamet.
Intervention code [1] 287079 0
Treatment: Drugs
Comparator / control treatment
All participants will undergo the malaria induced infection. 2 subjects will receive one dose of Mefloquine tablets (250 mg) 7 days after receiving the malaria inoculm. The Mefloquine control group is included to ensure that parasite growth and clearance with a drug of known activity is as expected.
Control group
Active

Outcomes
Primary outcome [1] 289490 0
The study also aims to characterise the effects of DSM265 on parasite clearance kinetics in healthy subjects following a blood stage infection with P. falciparum.
Timepoint [1] 289490 0
Week 4

This will be determined by the pharmacodynamics measurements.
Secondary outcome [1] 302604 0
Nil
Timepoint [1] 302604 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 45 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
45 Years
Sex
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. Positive direct antiglobulin test (direct Coomb’s test - DAT).
18. ALT and/or AST and/or lactase dehydrogenase (LDH) should be less than or equal to ULN.
19. Liver enzymes other than ALT, AST, LDH elevated greater than or equal to 1.5xULN within two (2) weeks prior to initial dosing.
20. Recent (within the last three [3] years) and/or recurrent history of autonomic dysfunction (e.g., recurrent episodes of fainting, palpitations, etc.).
21. 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).
22. History of any food allergies.
23. 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.
24. History or presence of impaired renal function as indicated by clinically significantly abnormal creatinine or urea values, or abnormal urinary constituents (e.g., albuminuria).
25. Evidence of urinary obstruction or difficulty in voiding at screening.
26. History of immunodeficiency diseases, including a positive HIV (ELISA and Western blot) test result.
27. A positive Hepatitis B surface antigen (HBsAg) or Hepatitis C test result.
28. 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.

In addition to all of the above exclusion criteria, subjects participating in the malaria induced infection phase (Part 2) must not fulfil any of the following exclusion criteria:
1. Have visited a malaria-endemic area for a period of greater than 2 weeks in the last 12 months.
2. Lives alone for the duration of the study.
3. Have ever received a blood transfusion.
4. Any clinically significant biochemical or haematologic abnormality (Hb must be greater than or equal to 11.5g/dL females; 13.5g/dL for males) – including pre-existing red cell antibodies.
5. Has evidence of increased cardiovascular disease risk (defined as greater than 10%, 5 year risk) as determined by the method of Gaziano et al. Risk factors include sex, age, systolic blood pressure (mm Hg),smoking status, body mass index (BMI, kg/m2), reported diabetes status and blood pressure
6. The volunteer is receiving psychiatric drugs or has been hospitalized within the past 5 years prior to enrollment for psychiatric illness, history of suicide attempt or confinement for danger to self or others. Participants who are receiving a single antidepressant drug and are stable for at least 3 months prior to enrollment without decompensating may be allowed to enroll in the study at the investigator’s discretion.
7. History or presence of suicidal behavior or any suicidal ideation of type 4 or 5 on the Columbia Suicide Severity rating Scale (C-SSRS) in the past 6 months or history of suicidality as assessed by the investigator.
8. History of a severe allergic reaction, anaphylaxis or convulsions following any vaccination or infusion.
9. Recent or current therapy with an antibiotic or drug with potential antimalarial activity (tetracyclines, clindamycin, hydroxychloroquine, azithromycin, amodiaquine, sulphonamides, co-trimoxazole, fluoroquinolones etc.).
10. Volunteers unwilling to defer blood donations to the ARCBS for 6 months.

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 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 number 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
Open (masking not used)
Who is / are masked / blinded?



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. After the completion of Part 1, if the pharmacokinetic parameters in Part 1 attain levels acceptable to the sponsor and Safety Review Team, the study will proceed to the induced malaria infection study (Part 2). Screening for Part 2 will begin 21 days prior to the end of Part 1. 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 (Part 3).
Phase
Phase 1
Type of endpoint/s
Pharmacokinetics / pharmacodynamics
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
1/05/2013
Actual
30/09/2013
Date of last participant enrolment
Anticipated
Actual
23/10/2013
Date of last data collection
Anticipated
Actual
Sample size
Target
10
Accrual to date
Final
9
Recruitment in Australia
Recruitment state(s)
QLD

Funding & Sponsors
Funding source category [1] 287211 0
Charities/Societies/Foundations
Name [1] 287211 0
Medicines for Malaria Venture
Country [1] 287211 0
Australia
Funding source category [2] 287214 0
Charities/Societies/Foundations
Name [2] 287214 0
Queensland Institute of Medical Research
Country [2] 287214 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] 285969 0
None
Name [1] 285969 0
Address [1] 285969 0
Country [1] 285969 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 289200 0
Queensland Institute of Medical Research Human Ethics Committee
Ethics committee address [1] 289200 0
The Queensland Institute of Medical Research,
Post Office Royal Brisbane,
QLD,
Australia,
4029
Ethics committee country [1] 289200 0
Australia
Date submitted for ethics approval [1] 289200 0
22/03/2013
Approval date [1] 289200 0
02/04/2013
Ethics approval number [1] 289200 0
P1523

Summary
Brief summary
This purpose of Part 2 of the study is to determine the activity of DSM265 (study drug) against malaria parasites in healthy subjects who have been inoculated with a low dose of malaria-infected red blood cells.

This trial is to be conducted under the Australian Therapeutic Goods Administration (TGA) Clinical Trial Notification Scheme (CTN).
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 39754 0
Prof James McCarthy
Address 39754 0
Q-Pharm Pty Limited, Level 5,
300C Herston Road,
Herston,
QLD,
Australia,
4006
Country 39754 0
Australia
Phone 39754 0
+61 7 3845 3796
Fax 39754 0
+61 7 3362 0104
Email 39754 0
[email protected]
Contact person for public queries
Name 39755 0
Gem Mackenroth
Address 39755 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 39755 0
Australia
Phone 39755 0
+ 61 7 3845 3629
Fax 39755 0
+61 7 3845 3630
Email 39755 0
[email protected]
Contact person for scientific queries
Name 39756 0
Suzanne Elliot
Address 39756 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 39756 0
Australia
Phone 39756 0
+61 7 3845 3644
Fax 39756 0
+61 7 3845 3637
Email 39756 0
[email protected]

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
Dimensions AISafety, tolerability, pharmacokinetics, and activity of the novel long-acting antimalarial DSM265: a two-part first-in-human phase 1a/1b randomised study2017https://doi.org/10.1016/s1473-3099(17)30171-8
EmbasePlasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitor Treatment of malaria.2019https://dx.doi.org/10.1358/dof.2019.44.2.2941689
N.B. These documents automatically identified may not have been verified by the study sponsor.