ANZCTR - Registration

Registration number

ACTRN12621001218886

Ethics application status

Approved

Date submitted

23/06/2021

Date registered

10/09/2021

Date last updated

16/11/2023

Date data sharing statement initially provided

10/09/2021

Type of registration

Prospectively registered

Titles & IDs

Public title

An Open-label, Single Ascending Dose Study of the Safety, Tolerability, and Pharmacokinetics of LYN-163 in Healthy Volunteers

Scientific title

An Open-label, Single Ascending Dose Study of the Safety, Tolerability, and Pharmacokinetics of LYN-163 in Healthy Volunteers

Secondary ID [1]

Protocol No.: LYN-163-C-101

Universal Trial Number (UTN)

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Malaria

Condition category

Condition code

Infection

Other infectious diseases

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Dosage form: Long-acting oral (LAO) capsule (LYN-163) containing 28 mg ivermectin in a drug-releasing formulation

Dosage:
• Cohort 0: single administration of one LYN-163 LAO capsule without stabilizing ring (dose of 28mg ivermectin)
• Cohort 1: single administration of one LYN 163 LAO capsule with stabilizing ring (dose of 28 mg ivermectin)
• Cohort 2: single administration of LYN 163 LAO capsules with stabilizing ring (dose of 56 mg ivermectin)

Route of administration: Oral

Administration instructions: LYN-163 capsules are to be taken orally after a light breakfast, while the participant is in a standing position. Participants in Cohort 1 will take the capsule with at least 250 mL of water immediately after capsule administration. Participants in Cohort 2 will take the first capsule with 125 mL of water immediately after capsule administration, and will then take the second capsule within 5 minutes of the first capsule, with an additional 125 mL of water immediately after administration. If the participant requests more fluid for swallowing, they may be given additional water in increments of 50 mL to chase. The volume of water consumed by the participant will be recorded in the eCRF. The participant is to remain upright after dosing for a total of at least 15 minutes to reduce the risk of delays in esophageal transit of the capsule. The participant must not bite or chew the capsule nor hold the capsule in the mouth before swallowing.

The following strategies will be used to monitor adherence to the intervention:. supervised administration, mouth checks, drug capsule return accountability.

This is an open-label, non randomized trial. The first 5 eligible participants were included in Cohort 0 (28mg dose) and the next 10 eligible participants will be included in Cohort 1 (28mg dose) and 10 more in Cohort 2 (56mg dose).

Intervention code [1]

Prevention

Intervention code [2]

Treatment: Drugs

Comparator / control treatment

Comparator: Cohort 2

Comparison will be made between Cohort 0, 1 (28mg dose- with and without stabilizing ring) and Cohort 2 (56mg dose). Both doses will be administered as described in the 'Description of interventions/exposure' section.

Control group

Dose comparison

Outcomes

Primary outcome [1]

Safety and tolerability of LYN-163assessed from the incidence of treatment-emergent adverse events (TEAEs) and clinical and laboratory assessments.

Both serious and non-serious AEs will be graded with respect to severity on the following 3 -point scale:

Mild: Discomfort noticed, but no disruption of normal daily activities; event usually requires no intervention.
Moderate: Discomfort sufficient to reduce or affect normal daily activities; event may require intervention.
Severe: Incapacitating, with inability to perform normal daily activities; event usually requires treatment or other intervention. Participant may not be able to continue in the study.

For final term coding MedDRA version V23.0 dictionary will be used.

The following vital signs will be assessed: heart rate assessed using a pulse oximeter, blood pressure measured using a sphygmomanometer, temperature using tympanic thermometer and respiratory rate using central timer.

The following laboratory tests will be performed: Clinical chemistry panel, Haematology panel and Coagulation tests (complete blood count with differential and HbA1c) by analysing a blood sample. Complete urinalysis by analysing urine sample. Fecal Occult Blood (by analysing of fecal specimen for the presence of fecal blood), Pregnancy test (by analysing blood and urine sample).

Timepoint [1]

Adverse Events: Screening (pre-dose), Day -1 (pre-dose), Day 1 (post-dose), Day 2 (post-dose), Day 3 (post-dose), Day 4 (post-dose), Day 5 (post-dose), Day 6 (post-dose), Day 7 (post-dose), Day 8 (post-dose), Day 9 (post-dose), Day 10 (post-dose), Day 12 (post-dose), Day 14 (post-dose), Day 16 (post-dose), Day 19 (post-dose), Day 22 (post-dose), Day 25 (post-dose) and Day 28 (End of Study (EOS)) or Early Termination Visit (ETV).

General physical examination: Screening (pre-dose), Day -1 (pre-dose), Day 7 (post-dose), Day 14 (post-dose) and Day 28 (post-dose) (EOS) or Early Termination Visit (ETV).

Directed physical examination: Day 1 (pre-dose), Day 2 (post-dose), Day 3 (post-dose), Day 4 (post-dose), Day 5 (post-dose), Day 6 (post-dose), Day 8 (post-dose), Day 9 (post-dose), Day 10 (post-dose), Day 12 (post-dose), Day 16 (post-dose), Day 19 (post-dose), Day 22 (post-dose) and Day 25 (post-dose).

Electrocardiogram: Screening (pre-dose), Day -1 (pre-dose), Day 1 (post-dose), Day 7 (post-dose) and Day 14 (post-dose).

Vital Signs: Screening (pre-dose), Day -1 (pre-dose), Day 1 (pre-dose and post-dose), Day 2 (post-dose), Day 3 (post-dose), Day 4 (post-dose), Day 5 (post-dose), Day 6 (post-dose), Day 7 (post-dose), Day 8 (post-dose), Day 9 (post-dose), Day 10 (post-dose), Day 12 (post-dose), Day 14 (post-dose), Day 16 (post-dose), Day 19 (post-dose), Day 22 (post-dose), Day 25 (post-dose) and Day 28 (post-dose) (End of Study) or Early Termination Visit.

Fecal Occult Blood Testing (FOBT): Screening (pre-dose) and Day 5 (post-dose).

Safety lab assessments: Screening (pre-dose), Day -1 (pre-dose), Day 7 (post-dose) and Day 14 (post-dose).

Secondary outcome [1]

Gastric residence and GI transit after administration of LYN-163 by ultrasound and X-ray imaging:
-Visualization and localization of LYN-163 formulation components characterized by each imaging assessment

GI exit properties of LYN-163 by X-ray imaging assessments and fecal recovery:
-Combination of lack of visualization of LYN-163 formulation and excreted components in feces.

This is a composite secondary outcome.

Timepoint [1]

Abdominal X-ray imaging: Day 3 (post-dose), Day 7 (post-dose), Day 10 (post-dose), Day 14 (post-dose), Day 22 (post-dose) and Early Termination Visit (if required).
Abdominal ultrasound: Day1 (post-dose), Day 2 (post-dose), Day 3 (post-dose), Day 6 (post-dose), Day 7 (post-dose), Day 10 (post-dose), Day 14 (post-dose) and Day 22 (post-dose).
Fecal assessment: Day 1 (post-dose), Day 2 (post-dose), Day 3 (post-dose), Day 4 (post-dose), Day 5 (post-dose), Day 6 (post-dose) and Day 7 (post-dose).

Secondary outcome [2]

PK of ivermectin metabolites after oral administration of LYN-163, to include where possible and appropriate: Cmax, Cmin, Tmax, Kel, AUC0-24, AUC0-t, AUC0-8, and AUC0-last.

Timepoint [2]

Blood PK sample collection at Day 1 (within 1 hr pre-dose) and Day 1 (1 hr post-dose), Day 1 (2 hr post-dose), Day 1 (4 hr post-dose), Day 1 (6 hr post-dose), Day 1 (8 hr post-dose), Day 1 (12hr post-dose), Day 1 (24hr post-dose), Day 2 (36 hr post-dose), Day 3 (48 hr post dose), Day 3 (60 hr post-dose), Day 4 (72 hr post-dose), Day 4 (84hr post-dose), Day 5 (96 hr post-dose), Day 5 (108 hr post-dose), Day 6 (120 hr post-dose), Day 6 (132 hr post-dose), Day 7 (144 hr post-dose) and Day 8 (168hr post-dose).

Blood PK sample collection at any timepoint on Day 9 (post-dose), Day 10 (post-dose), Day 12 (post-dose), Day 14 (post-dose), Day 16 (post-dose), Day 19 (post-dose), Day 22 (post-dose), Day 25 (post-dose) and Day 28 (End of Study) or Early Termination Visit.

Secondary outcome [3]

PK of ivermectin after oral administration of LYN-163, to include where possible and appropriate: Cmax, Cmin, Tmax, Kel, AUC0-24, AUC0-t, AUC0-8, and AUC0-last.

Timepoint [3]

Blood PK sample collection at Day 1 (within 1 hr pre-dose) and Day 1 (1 hr post-dose), Day 1 (2 hr post-dose), Day 1 (4 hr post-dose), Day 1 (6 hr post-dose), Day 1 (8 hr post-dose), Day 1 (12hr post-dose), Day 1 (24hr post-dose), Day 2 (36 hr post-dose), Day 3 (48 hr post dose), Day 3 (60 hr post-dose), Day 4 (72 hr post-dose), Day 4 (84hr post-dose), Day 5 (96 hr post-dose), Day 5 (108 hr post-dose), Day 6 (120 hr post-dose), Day 6 (132 hr post-dose), Day 7 (144 hr post-dose) and Day 8 (168hr post-dose).

Blood PK sample collection at any timepoint on Day 9 (post-dose), Day 10 (post-dose), Day 12 (post-dose), Day 14 (post-dose), Day 16 (post-dose), Day 19 (post-dose), Day 22 (post-dose), Day 25 (post-dose) and Day 28 (End of Study) or Early Termination Visit.

Eligibility

Key inclusion criteria

1. Men and women aged 18 to 49 years of age at the time of consent.
2. Individuals in good current health, in the Investigator’s opinion, as evidenced on review of medical history that includes no significant GI abnormalities, physical examination, concomitant medications, and other safety assessments.
3. Body weight greater than or equal to 56 kg.
4. Body mass index greater than or equal to 18.5 kg/m2 and less than or equal to 33 kg/m2.
5. Able to read and understand study procedures and provide written informed consent before the initiation of any protocol-specific procedures.
6. Willing to comply with all protocol-specified procedures and availability for the duration of the study.

Minimum age

18 Years

Maximum age

49 Years

Sex

Both males and females

Can healthy volunteers participate?

Yes

Key exclusion criteria

1. Individuals with known clinically significant esophageal or GI disease, including but not limited to:
a. Known strictures such as esophageal web, pyloric stenosis, or small intestinal stricture, or individuals with high risk of stricture, i.e., Crohn's disease.
b. Diagnosis of a condition known to elevate or lower gastric pH, e.g., achlorhydria or hypochlorhydria.
c. Prior varices or small or large bowel obstructions.
d. Prior abdominal or upper gastrointestinal surgery. (Prior uncomplicated laparoscopic procedures are permitted.)
e. History of dysphagia or aspiration in the last 5 years.
f. History of an esophageal motility disorder or undergoing treatment for a gastric motility disorder.
g. Multiple episodes of abdominal pain in the prior 3 months.
h. Moderate or severe dysmenorrhea or menorrhagia (with use of pain medication) in the prior 3 months.

2. History of moderate to severe Acid Reflux Disease or a score of greater than or equal to 2 on the Acid Reflux Severity Scale (ARSS), indicating moderate to severe symptoms. The ARSS scale is as follows:
None = 0 no symptoms.
Mild = 1 awareness of symptom, but easily tolerated.
Moderate = 2 discomfort sufficient to cause interference with normal activities.
Severe = 3 incapacitating, with inability to perform normal activities.

3. Individuals with PILL-5 questionnaire score of 5 or greater.
4. Medical history or current diagnoses indicating the presence of any of the following conditions:
a. Presence of an uncontrolled, unstable, clinically significant medical condition that could put the participant at risk because of participation in the study, interfere with the participant’s ability to participate in the study or influence the interpretation of safety or PK evaluations.
b. History of a major cardiovascular event (myocardial infarction, cardiac surgery or revascularization, unstable angina, stroke, or transient ischemic attack) or a hospitalization forheart failure within 6 months of Screening.
c. Any clinically significant illness, medical or surgical procedure, or trauma within 4weeks of Screening.
d. Known immunocompromised status, including individuals who have undergone organ transplantation, on immunosuppression therapy for an immune mediated disease, or are positive for human immunodeficiency virus (HIV).
e. Positive test for active hepatitis B or C at Screening. Individuals with successfully treated hepatitis B infection which has been resolved for greater than 1 year or successfully treated hepatitis C infection will not be excluded.
f. Donated more than 250 mL of blood within 4 weeks of Screening.
g. Difficulties with venipuncture/cannulation, including difficulty accessing veins for blood sampling and/or history of coagulopathy or endocarditis.
h. Active SARS-CoV-2 infection

5. Use of the following medications/treatments in the 2 weeks before enrollment, including:
a. Warfarin.
b. Proton pump inhibitors.
c. H2 blockers.
d. Prokinetic agents.
e. Concomitant medications, natural remedies, supplements, or vitamins. Use of antacids is permissible, except within 2 hours of dosing with LYN-163.
f. Non-steroidal anti-inflammatory drugs or acetylsalicylic acid.
g. Medications that may interfere with the absorption, metabolism, or excretion of ivermectin.
h. Hormonal contraceptives.

6. Use of blood products within 3 months of Screening.

7. Clinically significant abnormal safety (e.g.,physical examination, vital signs) or laboratory assessments at Screening, specifically:
a. Presence of a clinically significant abnormal laboratory result on blood or urine safety tests.
b. Anemia (hemoglobin below the lower limit of normal reference range).
c. Alanine aminotransferase (ALT), aspartate aminotransferase (AST) greater than or equal to 3.0 × the upper limit of normal (ULN), or total bilirubin greater than or equal to 1.5 × ULN.
d. Moderate or severe renal insufficiency (glomerular filtration rate <60mL/min, as determined using the Cockcroft-Gault formula).
e. Heart rate of <50 beats per minute (bpm).
f. Systolic blood pressure greater than or equal to 150 and/or diastolic blood pressure greater than or equal to 100mmHg.
g. Diabetes or HbA1c greater than or equal to 7.0 % at Screening.
h. Positive fecal occult blood test at Screening.
i. Thrombocytopenia (platelet count <150×109/L) or bleeding diathesis (INR >1.4) at Screening.
j. Creatine kinase >3 × ULN.

8. History of any drug or alcohol use disorder in the past 2years. Positive results for drugs of abuse or positive ethanol breathalyzer screen finding will exclude individuals unless the positive finding can be accounted for by documented prescription use. Exclusions include:
a. History of alcohol consumption exceeding moderate use; in males exceeding 21units per week and in females exceeding 14 units per week (1 unit is equal to 360 ml beer, 25 mL of 40% spirit or a 125 mL glass of wine) over the past month. Participants are not permitted to consume alcohol during the inpatient stay nor 12 hours before any clinic visit while an outpatient.
b. Current smokers, users of e-cigarettes, vaping products, or nicotine replacement products and individuals who have smoked within the last 12months. Positive results for cotinine are exclusionary.

9. Individuals of reproductive potential who are (hetero) sexually active but unwilling to use acceptable means of contraception through the EOS. For clarity, individuals who are at least 1 year post-menopausal are not of reproductive potential. Acceptable means of contraception include:
a. Individuals who have been surgically sterilized.
b. Females of reproductive potential: diaphragm, contraceptive sponge, or intrauterine device in use before enrollment.
c. Males: condom in combination with any of the above means of contraception for their female partners.
d. All individuals: abstinence.

10. Individuals who are nursing or who have a positive or indeterminate pregnancy test at either Screening (serum test) or enrollment (urine test).

11. Use of any experimental agent within 3 months or 5 half-lives of Screening, whichever is longer.

12. Employees or immediate family members of employees of the site, Sponsor, or study-related vendors.

13. History of hypersensitivity to LYN-163 components (ivermectin and excipients).

14. Individuals with history of X-ray, computed tomography scan,or angiogram of the abdomen within one year of Screening.

Study design

Statistical methods / analysis

General procedures:

A statistical analysis plan (SAP), providing details about the specific planned analyses and potential hypothesis tests, will be prepared and approved before study database lock. Both descriptive and inferential statistical methods may be used to fully explore the preliminary data. Summary statistics will be presented. Unless otherwise stated, categorical data will be presented using frequency counts and percentages, and continuous data will present number of participants, mean, standard deviation, median, minimum, and maximum. Geometric means and coefficients of variation will be displayed for PK data. AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) (v22.0 or a more recent version). Medications will be coded using the World Health Organization Drug Dictionary Enhanced Drug Reference List (2018).SAS 9.4 or higher (SAS Institute Inc., Cary NC USA) will be used for generating individual data listings, summary tables, and associated figures and for performing statistical analyses.

Sample size:

Cohort 0 enrolled 5 participants. Then 10 participants are planned to to be enrolled in cohort 1 and 10 more in cohort 2 to ensure at least 8 participants within a cohort have evaluable data for PK analysis. This study is exploratory in nature and is therefore not designed to test hypotheses. The sample size was driven by clinical rather than statistical considerations to provide sufficient data in the evaluation of the endpoints for LYN-163.

Analysis sets:

Enrolled Population is defined as all participants who are enrolled in the study and admitted to the research unit on Day -1. The Enrolled population will be used for reporting disposition and demographics. Safety Population (SAF) is defined as all enrolled participants who receive LYN-163on Day 1. The SAF will be the primary population in all safety and tolerability reporting. PK Population is defined as all enrolled participants who receive LYN-163and have at least 1 post dose quantifiable (or evaluable) PK concentration data.

Safety:

Analyses of safety data will be presented by cohort and study period and will be specified in the SAP. TEAEs are defined as events that started on or after the time of dosing with LYN-163 or existing events that worsened in severity or that became serious after receiving LYN-163. The number of participants with a TEAE and the number of events reported will be summarized by MedDRA system organ class and preferred term. SAEs, TEAEs leading to study discontinuation, TEAEs related to LYN-163and AECIs will also be summarized. AEs experienced by participants beforeLYN-163dosing on Day 1 will be listed. Laboratory evaluations, vital sign assessments, and ECG parameters will be summarized, including change from baseline. Baseline is defined as the last assessment beforeLYN-163dosing on Day 1. Abnormal laboratory findings will be flagged in participant listings. Changes in physical examinations will be listed for each participant. Prior and concomitant medications will be listed by participant.

Gastric residence, GI transit and GI exit will be assessed through abdominal ultrasound, X-rays and daily fecal assessments while in the clinical research unit. Summary tables and listings will be provided for the SAF population. The proportion of participants with X-ray data, visualization status of the stellate and location will be summarized by cohort. Retention will be defined as observing 3 or more component arms of the formulation in the stomach and in close proximity to each other and to the elastic core. Retention as assessed by X-ray, full recovery and/or partial recovery of the stellate as assessed by daily fecal assessments and X-ray confirmation will be provided by cohort.

Efficacy:

PK analyses will be conducted with the PK population, which will include all participants who received study drug and who have sufficient PK samples collected to generate PK parameters. Plasma concentration data for ivermectin and relative quantities for metabolites will be listed and tabulated and plotted for each participant for whom concentrations are quantifiable. PK parameters will be estimated where data are sufficient for estimation. A separate PK analysis plan may be created to provide the details about the PK and the PKPD analyses.

PK-PD analyses: Mosquito survival at each time point will be compared to baseline within each treatment regimen using Log-Rank survival curve analysis (Mantel-Cox method). Mosquito mortality will be linked to measured ivermectin concentrations to determine the lethal concentration that kills50% of mosquitoes (LC50) using a normalized concentration-response analysis (IC50and Hill). Pharmacokinetic-pharmacodynamic (PK-PD) models will be created to explain the dynamic relationship between ivermectin concentrations and mosquito mortality over time. The population PK and PD analyses will be performed using nonlinear mixed-effects modeling in NONMEM (Icon Development Solution, Ellicott City, MD). R, Xpose, Pirana, and Pearls-peaks-NONMEM will be used for model diagnostics and visualization of results. The difference in objective function value will be used as a statistical criterion for discrimination between nested models. The difference in the Bayesian information criterion will be used when comparing non-nested models. The PK properties will be characterized by evaluating different absorption and disposition models, as well as the influence of covariates, such as body weight and age. Predicted ivermectin and metabolite concentrations at the time of mosquito-feeding will be used to link drug exposure to mosquito mortality (cumulative mortality at day 10), by applying a concentration-response model (Emax model). The final PK-PD model can be used for clinical trial simulations to inform future clinical trials.

Recruitment

Recruitment status

Completed

Date of first participant enrolment

Anticipated

15/10/2021

Actual

26/05/2022

Date of last participant enrolment

Anticipated

28/02/2023

Actual

18/01/2023

Date of last data collection

Anticipated

15/04/2023

Actual

14/02/2023

Sample size

Target

25

Accrual to date

Final

15

Recruitment in Australia

Recruitment state(s)

SA

Recruitment hospital [1]

CMAX Clinical Research Pty Ltd - Adelaide

Recruitment postcode(s) [1]

5000 - Adelaide

Funding & Sponsors

Funding source category [1]

Commercial sector/Industry

Name [1]

Lyndra®Therapeutics, Inc. (Lyndra)

Country [1]

United States of America

Primary sponsor type

Commercial sector/Industry

Name

Lyndra®Therapeutics, Inc. (Lyndra)

Country

United States of America

Secondary sponsor category [1]

Commercial sector/Industry

Name [1]

Novotech (Australia) Pty Ltd

Country [1]

Australia

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Bellberry Limited

Ethics committee address [1]

123 Glen Osmond Road
Eastwood, South Australia 5063

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

02/06/2021

Approval date [1]

02/07/2021

Ethics approval number [1]

2021-01-194

Summary

Brief summary

Lyndra Therapeutics is currently developing LAO capsules for weekly administration across therapeutic areas with certain medications for which simplified logistics of dosing and/or consistent pharmacokinetics (PK) or enhanced adherence may translate to improved efficacy and possibly better safety.

The LYN-163ER capsule is designed to provide steady, extended release of ivermectin into the stomach by gradually eluting the drug from a non-dissolving form that stays in the stomach for approximately 2weeks. Central to this goal is the need for a dosage form capable of safely remaining within the stomach for 2weeks. Equally important are the requirements of safe passage into the stomach after swallowing: opening of the capsule in the stomach to release the formulation (stellate), controlled drug release, and safe exit and passage out of the stomach and through the intestinal tract.

This single ascending dose study will evaluate the safety, tolerability, pharmacokinetics (PK) of LYN-163in healthy individuals. The PK of ivermectin will be assessed. Data from this study will be a key indicator of feasibility of the product concept and will inform formulation optimization and dose selection for further development. This study will enroll individuals who are in good health. Healthy volunteers are most suitable for providing the initial characterization of the LYN-163safety and PK profile after a single dose.

This is an open-label study that will enroll 3 cohorts, each with 5-10 participants. Cohort 0 had 5 participants and cohort 1 and 2 will have 10 participants in each cohort.  Cohort 1 and 2 will include 2 participants in a sentinel group and 8 participants in a main group. In each cohort, safety data through Day 5 post dose for both participants in the sentinel group will be reviewed by the Investigator before enrollment of participants in the main group begins. Enrollment of sentinel participants in Cohort 2 will not begin until review of safety data through Day 5 post dose from both participants in the sentinel group in Cohort 1.

Trial website

Public notes

COVID-19 vaccine is prohibited during the study.

Contacts

Principal investigator

Name

Dr Michele De Sciscio

Address

CMAX Clinical Research
Level 5, 18a North Terrace
Adelaide, South Australia 5000

Country

Australia

Phone

+61 422447902

Email

michele.desciscio@sa.gov.au

Contact person for public queries

Name

Michele De Sciscio

Address

CMAX Clinical Research
Level 5, 18a North Terrace
Adelaide, South Australia 5000

Country

Australia

Phone

+61 422447902

Email

michele.desciscio@sa.gov.au

Contact person for scientific queries

Name

Patrick G Boen

Address

VP, Clinical development
Lyndra Therapeutics, Inc.
65 Grove street
Suite 301
Watertown, MA 02472

Country

United States of America

Phone

+1 862 251 1544

Email

pgoen@lyndra.com

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