The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial registered on ANZCTR


Registration number
ACTRN12619000372189
Ethics application status
Approved
Date submitted
21/01/2019
Date registered
11/03/2019
Date last updated
11/06/2019
Date data sharing statement initially provided
11/03/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Phase 1b study to determine the safety, tolerability and pharmacokinetics of
RTB101 and sirolimus alone or in combination in patients with Mild Parkinson’s Disease (PD).
Scientific title
A Multicenter, Patient and Investigator-Blinded, Placebo-Controlled Proof-Of-Concept
Study to Determine the Safety, Tolerability and Central Nervous System (CNS) Exposure
of Oral RTB101 and Sirolimus Alone or in Combination in Patients with Mild-Moderate
Parkinson’s Disease (PD).
Secondary ID [1] 297146 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Parkinson's disease 311176 0
Condition category
Condition code
Neurological 309796 309796 0 0
Parkinson's disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
• Cohort 1: RTB101 300 mg capsule given orally once per week for up to 4 weeks.
• Cohort 2: Sirolimus 2 mg tablet given orally once per week for up to 4 weeks.
• Cohort 3: RTB101 300 mg capsule + sirolimus 2 mg tablet given orally once per week for up to 4 weeks.
• Cohort 4: RTB101 300 mg capsule + sirolimus 4 mg tablet given orally once per week for up to 4 weeks.
• Cohort 5: RTB101 300 mg capsule + sirolimus 6 mg tablet given orally once per week for up to 4 weeks.

Compliance will be assessed by the investigator and/or study personnel at each visit by having patients bring remaining study drug to each visit. The site staff will count the remaining number of capsules and/or tablets and record this information in the CRF.

Cohorts 1 and 2 may be enrolled in parallel, and dose escalation Cohorts 3-5 will enroll sequentially.
Intervention code [1] 313407 0
Treatment: Drugs
Comparator / control treatment
Lactose monohydrate 83.62 mg
Polyvinylppyrrolidone 0.39 mg
Crospovidone 0.49 mg
Starch 14.0 mg
Colloidal silicon dioxide 0.50 mg
Magnesium stearate 1.0 mg
Control group
Placebo

Outcomes
Primary outcome [1] 318757 0
Percentage of patients experiencing one or more treatment-emergent adverse events in the treatment arms compared to the placebo arms.
Adverse events that may occur: diarrhoea, nausea, abdominal discomfort, oral discomfort, abdominal pain, flatulence, regurgitation, vomiting, headache.
Adverse events will be reported by patients at study visits.
Timepoint [1] 318757 0
From the first dose of the study drug (at Day 0 visit) until Week 4 visit.
Primary outcome [2] 318758 0
Clinically significant changes in clinical laboratory values (eg haematology, blood chemistry urinalysis) or other clinical parameters (e.g. vital signs including body temperature, respiratory rate, blood pressure (supine and standing), pulse rate (supine and standing)) from the baseline value.
Timepoint [2] 318758 0
From the first dose of the study drug (at Day 0 visit) until Week 4 visit.
Secondary outcome [1] 365938 0
Drug concentrations in blood and plasma.
Timepoint [1] 365938 0
Day 0: 1h pre-dose; 1h, 2h, 4h post dose; Week 1: 8h post dose, Week 2: 24h post dose, Week 3 : 1h pre-dose; 1h, 2h, 4h post dose; Week 4 - anytime >4 days following last dose at Week 4 visit
Secondary outcome [2] 365939 0
CSF concentrations of RTB101 and sirolimus given alone or in combination after oral administration once weekly in PD patients.
Timepoint [2] 365939 0
At Week 3 (4 hours post dosing)

Eligibility
Key inclusion criteria
- Patient must be able to communicate well with the Investigator, and to
understand and comply with the requirements of the study.
- Signed informed consent must be obtained before any study assessment is
performed.
- Male and female adults 18 years of age and older at the time of informed
consent signing
- Patients must weigh greater than or equal to 40 kg and less than or equal to 150 kg at Baseline Visit.
- Diagnosis of PD with a mH&Y stage of less than or equal to 2 at screening
- Stable medication regimen of PD drugs for at least 30 days (at least 60
days for rasagiline) prior to first dose (Day 0, Visit 3).
- At screening and baseline, vital signs (systolic and diastolic blood
pressure (BP), pulse rate and body temperature) will be assessed in a sitting
position after the patient has rested for at least three minutes. Sitting vital
signs must be within the following ranges:
• Oral or tympanic body temperature between 35.0-37.5°C
• Systolic BP, 90-160 mm Hg
• Diastolic BP, 50-95 mm Hg
• Heart rate, 40-95 bpm
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
-Parkinsonism due to drug(s) or toxin(s) or with history of a prior brain
magnetic resonance imaging (MRI) without contrast, showing a structural
abnormality that is a possible cause of their PD signs or symptoms
-Patients with prior surgical history of deep brain stimulation (DBS).
-If female, pregnancy (defined as positive beta-human chorionic
gonadotrophin [b-hCG] blood test), lactating or breast-feeding.
-Women of childbearing potential (any woman physiologically capable of
becoming pregnant) unless they remain on highly effective methods of
contraception (see below) throughout the study and for 12 weeks
following discontinuation of the study drug.
-Sexually active male patients with a partner of childbearing
potential must be willing to wear a condom while on study drug
and for 12 weeks after stopping study drug and should not father a child
in this period. A condom is required to be used also by vasectomized men
with a partner of child-bearing potential in order to prevent delivery of
the drug via seminal fluid.
-Use of other investigational drugs within 5 half-lives of randomization, or
within 30 days, whichever is longer; or longer if required by local
regulations.
-History of hypersensitivity or allergy to sirolimus, RTB101 or their
excipients or to other mTOR inhibitor drugs.
-Concomitant use of any of the drugs (including strong CYP3A4 inhibitors or inducers, angiotensin-converting-enzyme (ACE) inhibitors, anti-coagulants) or other treatments (including live vaccines)
-Any one of the following hematologic or coagulation abnormalities at
screening:
• Haemoglobin <10.0 g/dL for males and <9.0 g/dL for females
• White blood cell count (WBC) <3,500/mm3
• Neutrophil count <2,000/mm3
• Platelet count <125,000/mm3
• International normalized ratio (INR) >1.2
• Partial prothromboplastin time (PTT) >35 seconds.
-Patients receiving immunosuppressive therapy including chronic use of
prednisone >10 mg daily.
- Patients with active or chronic infection other than fungal skin or nail infection or local herpes simplex infection.
-Immunodeficiency diseases, including a positive human immunodeficiency virus (HIV) test result; or chronic infection with Hepatitis B virus (HBV) or Hepatitis C virus (HCV).
-Recent surgery (involving entry into a body cavity or requiring sutures) within 2 months of the Screening Visit or any evidence of unhealed surgical wound or lack of significant recovery from the surgery (minor skin surgery is allowed within 2 months of Screening provided the surgical wound has healed).
-Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of drugs, or which may jeopardize the patient in case of participation in the study.
-Patients with insulin-dependent diabetes mellitus (Type 1 or 2)
-Patients with significant uncontrolled hypercholesterolemia
-History of malignancy in any organ system, treated or untreated, within the past 3 years, regardless if there is evidence of local recurrence or metastases, except for localized basal cell or squamous cell carcinoma of the skin. History of malignancy in any organ system, treated or untreated, within the past 3 years, regardless if there is evidence of local recurrence or metastases, except for:
• Treated localized basal cell carcinoma of the skin.
• Prostate cancer confined to the gland (AJCC stage T2N0M0 or better).
• Treated cervical carcinoma in situ.
• Treated breast cancer localized to the breast.
-Patients with clinically significant underlying pulmonary disease other than asthma.
The following cardiac conditions:
a) Unstable angina pectoris or acute ischemic changes on ECG at Screening.
b) History of myocardial infarction, coronary bypass surgery, or any percutaneous coronary intervention (PCI) within 6
months prior to Screening.
c) Ventricular arrhythmias except for benign premature ventricular contractions.
d) New York Heart Association functional classification III-IV congestive heart failure.
- Any other medical condition, as judged by the Investigator, that is likely to interfere with the patient’s participation in the study, or likely to cause serious adverse events (SAEs) during the study.


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)
Central randomisation by computer (Interactive Response Technology)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
2:1 Active vs. Placebo block randomisation using a computer software (i.e. computerised sequence generation)
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
Intervention assignment
Other
Other design features
Cohorts 1 and 2 may be enrolled in parallel, and Cohorts 3-5 will enroll sequentially.
Phase
Phase 1 / Phase 2
Type of endpoint(s)
Safety
Statistical methods / analysis
Mixed-effects (population) methods.
Intention-to-treat 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 outside Australia
Country [1] 21216 0
New Zealand
State/province [1] 21216 0

Funding & Sponsors
Funding source category [1] 301703 0
Commercial sector/Industry
Name [1] 301703 0
resTORbio, Inc.
Address [1] 301703 0
500 Boylston Street
12th Floor
Boston, MA 02216 USA
Country [1] 301703 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
resTORbio, Inc.
Address
500 Boylston Street
12th Floor
Boston, MA 02216 USA
Country
New Zealand
Secondary sponsor category [1] 301428 0
Commercial sector/Industry
Name [1] 301428 0
Pharmaceutical Solutions Ltd
Address [1] 301428 0
Level 1, The Levy Building, 20 Customs Street East, AKL 1010
Country [1] 301428 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 302424 0
Southern Health and Disability Ethics Committee
Ethics committee address [1] 302424 0
Ministry of Health
Health and Disability Ethics Committees
PO Box 5013
Wellington 6140
Ethics committee country [1] 302424 0
New Zealand
Date submitted for ethics approval [1] 302424 0
31/01/2019
Approval date [1] 302424 0
18/03/2019
Ethics approval number [1] 302424 0

Summary
Brief summary
The purpose of this study is to determine if up to 4 weeks of once weekly oral dosing of RTB101 and sirolimus given alone or in combination is safe, tolerable and achieves potentially therapeutic exposures in the CNS (central nervous system) of patients with mild (modified Hoehn and Yahr [mH&Y] stage less than or equal to 2) Parkinson’s disease (PD)
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 90186 0
Prof Tim Anderson
Address 90186 0
New Zealand Brain Research Institute
66 Stewart Street, Christchurch Central, New Zealand, 8011
Country 90186 0
New Zealand
Phone 90186 0
+64 03 3786079
Fax 90186 0
Email 90186 0
tim.anderson@cdhb.health.nz
Contact person for public queries
Name 90187 0
Prof Tim Anderson
Address 90187 0
New Zealand Brain Research Institute
66 Stewart Street, Christchurch Central, New Zealand, 8011
Country 90187 0
New Zealand
Phone 90187 0
+64 03 3786079
Fax 90187 0
Email 90187 0
tim.anderson@cdhb.health.nz
Contact person for scientific queries
Name 90188 0
Prof Tim Anderson
Address 90188 0
New Zealand Brain Research Institute
66 Stewart Street, Christchurch Central
8011
New Zealand
Country 90188 0
New Zealand
Phone 90188 0
+64 03 3786079
Fax 90188 0
Email 90188 0
tim.anderson@cdhb.health.nz

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
No other documents available
Summary results
No Results