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Trial registered on ANZCTR


Registration number
ACTRN12619001569190
Ethics application status
Approved
Date submitted
22/10/2019
Date registered
13/11/2019
Date last updated
13/11/2019
Date data sharing statement initially provided
13/11/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Study to Evaluate Safety, Tolerability, and Pharmacokinetics of Risperidone Extended Release Capsules in Patients with Schizophrenia, Schizoaffective Disorder or Bipolar 1 Disorder
Scientific title
Open-Label Single Dose Pilot Study to Assess Safety, Tolerability and Pharmacokinetics of Risperidone Extended Release Capsules in Patients with Schizophrenia, Schizoaffective Disorder or Bipolar 1 Disorder
Secondary ID [1] 299539 0
LYN-005-C-001
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Schizophrenia 314797 0
Schizoaffective disorder 315055 0
Bipolar 1 disorder 315056 0
Condition category
Condition code
Mental Health 313135 313135 0 0
Schizophrenia
Mental Health 313335 313335 0 0
Other mental health disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The intervention is LYN-005, a single extended release (ER) capsule containing risperidone (14 mg). The rationale for the development of this ER capsule is to reduce the frequency of dosing orally administered risperidone medications to once weekly or less and thereby improving the management of schizophrenia.
LYN-005, to be administered, is a single Size 00EL capsule, containing 14 mg risperidone (a proposed weekly dose), within the ER formulation (stellate).
While inpatient, on Day -3 to Day -1, a 2 mg RISPERDAL IR tablet will be orally administered daily to each participant.
On Day 1 (no Day 0), one LYN-005 capsule will be orally administered to the participant. The single capsule will be administered by a trained nurse (at a minimum) in a clinic for the Sentinel (first participant) and Main (remaining participant) groups. If required, dropouts will be replaced at the discretion of the PI.
On Day 8 while still within the inpatient facility, participants will return to their daily outpatient RISPERDAL administration until discharge (Day 12).
Intervention code [1] 315793 0
Treatment: Drugs
Comparator / control treatment
No control group,
Control group
Uncontrolled

Outcomes
Primary outcome [1] 321665 0
Safety and tolerability of a LYN-005 ER capsule assessed from a combination of the following:
- Incidence and severity of adverse events (AEs) and serious adverse events (SAEs), treatment-related and treatment emergent AEs, AEs leading to withdrawal, AEs of Special Interest (AESI), death, concomitant medications, safety laboratory tests, physical examinations, vital signs and electrocardiograms (ECGs).
and
- Extrapyramidal Symptom Rating Scale (ESRS), assessment of global function Clinical Global Impression-Severity (CGI-S), suicidality using the Columbia-Suicide Severity Rating Scale (C-SSRS)
Timepoint [1] 321665 0
Adverse events and vital signs will be conducted daily for the duration an inpatient admission for observation after dosing, at discharge and on follow-up visits on Day 18 and Day 28. Concomitant medications will be tracked throughout, i.e., from the time of screening, admission into the inpatient stay (Day 11), through discharge (Day 12) and at follow-up visits on Day 18 and Day 28. Directed physical exams will be performed at admission, Day 11, Day 12 (discharge) and follow-up visits on Day 18 and Day 28. ECGs will be performed at admission, on Days -1, Day 1 (at time of dosing and at 4 hours post dose), Day 4 and Day 11. Safety laboratory assessments will be conducted at admission, Day 1, Day 4 and Day 11.

ESRS will be assessed at screening, admission, while in patient on Day -1, Day 1, Day 3, Day 5, Day 7, Day 11 and at the End of Study (EOS) (Day 28).
CGI-S will be conducted at screening, admission, while in patient on Day -1, Day 1, Day 3, Day 5, Day 7, Day 11 and at follow-up visits on Day 18 and Day 28 (EOS).
C-SSRS will be assessed at screening, admission, while in patient on Day -1, Day 11 and at follow-up visits on Day 18 and Day 28.
Primary outcome [2] 321746 0
As a composite primary outcome, risperidone, 9-hydroxyrisperidone and active moiety pharmacokinetics, e.g., Cmax, Cmin, AUC0-168, AUC0-inf, after oral administration of a LYN-005 capsule and immediate-release (IR) risperidone using a validated serum assay.
Timepoint [2] 321746 0
Upon admission to the unit, (Day-4 of LYN-005)
Day -3 to Day -1 (of LYN-005): daily before breakfast
Day-1 (following 2 mg IR dose): dense PK sampling at 15, 30, 45 minutes and at 1, 2, 4, 6, 8, 12, and 16 hours post-dose
Day 1, at breakfast prior to dosing LYN-005, Thereafter, at 1, 2, 4, 6, 8, 12, 24, 26, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, 216 hours post dose. (after Day 1, every 12 hours post dose through Day 10)
Secondary outcome [1] 376086 0
Gastrointestinal transit of LYN-005 capsules by X-ray.
Timepoint [1] 376086 0
Day 5
Day 8
Day 18

Eligibility
Key inclusion criteria
1. Current diagnosis of schizophrenia or schizoaffective disorder or bipolar 1 disorder according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria as confirmed by the MINI 7.0.2
2. The following psychiatric criteria are to be used to determine participant eligibility:
- Duration of diagnosis of schizophrenia or schizoaffective disorder or bipolar 1 disorder of 2 years, unless a shorter period is deemed appropriate by the PI;
- Outpatient; not hospitalised for worsening of schizophrenia within the last 6 months (hospitalisation for social management within this time period is acceptable), unless a shorter period is deemed appropriate by the PI;
- Medically stable over the last month and psychiatrically stable without significant symptom exacerbation over the last 3 months based on the investigator's judgement, unless a shorter period is deemed appropriate by the PI;
3. On oral risperidone 2-4 mg once daily as maintenance therapy for at least 6 weeks prior to screening;
4 Participants with bipolar 1 disorder receiving mood stabilisers must be receiving stable doses of the following permitted agents for at least 6 weeks prior to screening: valproic acid, lithium carbonate or lamotrigine;
5. On a stable dosage of all permitted medications (except for medication to be used on an as-needs basis) for at least 1 month prior to the screening visit and for the duration of the study;
6. Clinical Global Impression - Severity (CGI-S) score of less than or equal to 4 (moderately ill);
7. Participants who, in the opinion of the Investigator, do not have significant underlying gastrointestinal abnormalities at the time of screening;
8. Body mass index (BMI) of greater than or equal to 18 kg/meters squared and less than or equal to 35 kg/meters squared, and with a body weight between 50 and 120 kg;
9. Men and women of childbearing potential must agree to use a highly effective method of contraception throughout the duration of the study (through Day 28);
10. Female patients must have a negative pregnancy test at screening (serum test) and baseline (urine test);
11. Psychotherapy should not be started or changed during a patient's participation in the study. It is acceptable for a patient already receiving psychotherapy to participate in the study;
12. Must be able to read and understand study procedures, and provide written informed consent prior to the initiation of any protocol-specific procedures;
Minimum age
18 Years
Maximum age
49 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Presence of an uncontrolled, unstable, clinically significant medical condition (e.g., renal, endocrine, hepatic, respiratory, cardiovascular, haematologic, immunologic or cerebrovascular disease, or malignancy) that in the opinion of the investigator could interfere with the interpretation of safety and PK evaluations;
2. Individuals with a current DSM-5 diagnosis of major depressive episode, recent manic and hypomanic episode (excluding bipolar 1 disorder participants), panic disorder, agoraphobia, social anxiety disorder, obsessive-compulsive disorder, post-traumatic stress disorder, generalised anxiety disorder on the MINI, version 7.0.2, or in the judgment of the investigator;
3. Receiving an antipsychotic drug other than risperidone;
4. Presence of a clinically significant vital sign or physical examination finding that in the opinion of the investigator could potentially interfere with the ability to evaluate safety and tolerability of the trial medication or could impair the patient's ability to complete the trial;
5. Presence of a clinically significant abnormality on blood or urine safety tests, which do not improve on re-testing;
6. If female, a positive serum pregnancy test, or planning to become pregnant during the trial, between signing informed consent and Day 28 (End of Study Visit), or is breastfeeding a child;
7. History of Hepatitis B infection within the past year, or history of Hepatitis C infection that has not been adequately treated;
8. History of neuroleptic malignant syndrome;
9. Current or history of clinically significant tardive dyskinesia;
10. Positive urine drug/alcohol screen finding, unless the positive finding can be accounted for by documented prescription use or is permitted at the investigator’s discretion.
11. Fulfilment of the DSM-5 criteria for moderate or severe substance use disorder (excluding nicotine) within the past 6 months;
12. In the investigator's opinion, at imminent risk of committing self-harm or harm to others, based on clinical interview and responses provided on the Columbia-Suicide Severity Rating Scale (C-SSRS). Individuals will be excluded if they report having suicidal ideation associated with actual intent and a method or plan in the past 6 months, as measured by the C-SSRS (i.e., “Yes” answers on items 4 or 5) at screening or baseline;
13. Use of depot antipsychotics within the last 9 months;
14. Use of moderate or strong cytochrome P450 3A4 (CYP3A4) p-glycoprotein (P-gp) enzyme inducers and inhibitors (carbamazepine, phenytoin, rifampicin, phenobarbital, itraconazole, verapamil) or moderate or strong cytochrome P450 2D6 (CYP2D6) inhibitors (e.g., fluoxetine, fluoxetine combinations, paroxetine) within 30 days prior to baseline;
15. Use of any investigational drugs within the last 3 months;
16. Current or past participation in any other clinical trial in the past 30 days;
17. Known or suspected allergy or hypersensitivity to risperidone;
18. Serious adverse reaction or serious hypersensitivity to components of the study formulations or patency capsule;
19. Previous non-responder to risperidone treatment or treatment refractory schizophrenia, defined as failure of more than 2 adequate trials of second-generation atypical or typical antipsychotics;
20. Individuals with clinically significant oesophageal or gastrointestinal disease (including irritable bowel syndrome) or have symptoms suggestive of functional constipation or diarrhoea;
21. Individuals with gastrointestinal transit times, as assessed by administration of a patency pill, of either a) an Oesophageal Transit Time (ETT), defined as the time to reach the stomach, greater than 30 ±5 seconds, or b) a gastrointestinal transit time (GTT), defined as the time to reach the colon or exit the body, greater than 30 + 1 hours;
22. CYP2D6 poor or undetermined metaboliser status based on genetic testing.
23. Individuals who have made a suicide attempt within the last 5 years.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 1
Type of endpoint(s)
Safety
Statistical methods / analysis

Recruitment
Recruitment status
Not yet 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 in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 15028 0
Albert Road Clinic - Melbourne
Recruitment postcode(s) [1] 28314 0
3004 - Melbourne

Funding & Sponsors
Funding source category [1] 304029 0
Commercial sector/Industry
Name [1] 304029 0
Lyndra Australia Pty Ltd
Address [1] 304029 0
Level 13 41 Exhibition Street
Melbourne VIC 3000
Country [1] 304029 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Lyndra Australia Pty Ltd
Address
Level 13 41 Exhibition Street
Melbourne VIC 3000
Country
Australia
Secondary sponsor category [1] 304208 0
None
Name [1] 304208 0
Address [1] 304208 0
Country [1] 304208 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 304520 0
Bellberry Limited HREC Committee C
Ethics committee address [1] 304520 0
123 Glen Osmond Rd
Eastwood South Australia 5063
Ethics committee country [1] 304520 0
Australia
Date submitted for ethics approval [1] 304520 0
07/05/2019
Approval date [1] 304520 0
05/09/2019
Ethics approval number [1] 304520 0
2019-05-380

Summary
Brief summary
To evaluate the safety of LYN-005 extended release capsules containing risperidone in patients with schizophrenia, schizoaffective disorder or bipolar 1 disorder.
To perform characterisation of the the pharmacokinetics of risperidone and active metabolite, 9-hydroxyrisperidone, and active moiety administered as a LYN-005 extended-release (ER) capsule of risperidone to immediate-release (IR) risperidone tablets
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 97242 0
Dr Malcolm Hopwood
Address 97242 0
Ramsay Healthcare (Victoria) Pty. Ltd. T/A Albert Road Clinic
31-33 Albert Rd,
Melbourne VIC 3004
Country 97242 0
Australia
Phone 97242 0
+61 0392793518
Fax 97242 0
Email 97242 0
mhopwood@unimelb.edu.au
Contact person for public queries
Name 97243 0
Ms Jessica Ballinger
Address 97243 0
(Director)
Lyndra Australia Pty Ltd
Level 13 41 Exhibition St
Melbourne VIC 3000
Country 97243 0
Australia
Phone 97243 0
+1 857 201 5322
Fax 97243 0
Email 97243 0
jballinger@lyndra.com
Contact person for scientific queries
Name 97244 0
Dr Bernard Silverman
Address 97244 0
Lyndra Therapeutics Inc
65 Grove St
Suite 301
Watertown MA 02472
Country 97244 0
United States of America
Phone 97244 0
+1 617 803 2445
Fax 97244 0
Email 97244 0
bsilverman@lyndra.com

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Individual participant data underlying published results only
When will data be available (start and end dates)?
3 months following publication, 4 years following publication
Available to whom?
case by case basis at the discretion of the Lyndra (primary sponsor)
Available for what types of analyses?
only to achieve the aims in the approved proposal
How or where can data be obtained?
required to sign data access agreement by emailing the primary sponsor (jdube@lyndra.com)
What supporting documents are/will be available?
No other documents available
Summary results
No Results