First-in-human Study to Assess the Safety and Pharmacokinetics of LML134 in Healthy Volunteers

Healthy Volunteers Clinical Trial

— LML134  

Official title:

A First-in-human, Randomized, Double-blind, Placebo-controlled, Single and Multiple Ascending Oral Dose Study, to Assess the Safety, Tolerability and Pharmacokinetics of LML134 in Healthy Volunteers

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02334449
• Other study ID #: CLML134X2101
• Secondary ID: 2014-000937-22
• Status: Completed
• Phase: Phase 1
• First received: November 14, 2014
• Last updated: October 26, 2016
• Start date: February 2015
• Est. completion date: February 2016

Study information

• Verified date: October 2016
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Health authority: Unites Kingdom: Medicines and Healthcare products Regulatory Agency (MHRA)
• Study type: Interventional

Clinical Trial Summary

Phase I study to assess the safety, tolerability and pharmacokinetics of ascending single and multiple doses of the investigational medicinal product in healthy volunteers

Recruitment information / eligibility

• Status: Completed
• Enrollment: 133
• Est. completion date: February 2016
• Est. primary completion date: February 2016
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 18 Years to 55 Years

Eligibility

Inclusion Criteria:

• Healthy male and female subjects age 18 to 55 years of age included, and in good health as determined by medical history, physical examination, vital signs, electrocardiogram, and laboratory tests.

• Written informed consent must be obtained before any assessment is performed.

• Able to communicate well with the Investigator, to understand and comply with the requirements of the study.

Exclusion Criteria:

• History or presence of epilepsy or of seizures or convulsions of any kind.

• Any clinically relevant abnormalities identified in the resting EEG during screening, or pre-ictal signs or other clinically relevant abnormalities in the hyperventilation or intermittent photic stimulation EEG during screening.

• History of head trauma leading to clinically significant symptoms in the past two years.

• Applies only to subjects enrolled in Part 2 MAD. Score "yes" on item 4 or item 5 of the Suicidal Ideation section of the C-SSRS, if this ideation occurred in the past 6 months, or "yes" on any item of the Suicidal Behavior section, except for the "Non-Suicidal Self-Injurious Behavior" (item also included in the Suicidal Behavior section), if this behavior occurred in the past 2 years.

• Significant illness including any clinically significant infectious disease which has not resolved within two (2) weeks prior to initial dosing.

• History or presence of significant hematological abnormalities or immunodeficiency or any condition that might compromise the immune system (infection, vaccination), of any etiology as indicated by clinically significantly abnormal values of any of the following hematologic parameters: thrombocyte, RBC count, total WBC count and differentials presented as % of total white blood cell count and as absolute concentrations.

• History or presence of any thyroid disease as indicated by any clinically relevant abnormality on thyroid stimulating hormone test (TSH).

• History or presence of any chronic eye disease other than refractive error, strabismic amblyopia, or anisometropic amblyopia.

• Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant.

Study Design

Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Healthy Volunteers

Intervention

Drug:
• LML134
LML134 will be administered first as single doses and then as multiple doses
• Placebo
All study cohorts (except food effect cohort) are placebo controlled

Locations

Country	Name	City	State
Germany	Novartis Investigative Site	Berlin

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Adverse events assessments after single and multiple ascending dose administration at baseline and repeatedly until study completion	This safety outcome combines the measure of the number of subjects experiencing adverse events (AEs), the nature and severity of those AEs and their relationship to the study treatments.	Starting about 24 hours before dosing and continued until about 7-14 days after last dose	Yes
Primary	Cardiovascular safety assessments after single and multiple ascending dose administration at baseline and repeatedly until study completion	This safety outcome combines the measure of a set of cardiovascular safety parameters extracted from ECGs, 25 hours-Holter ECGs and from vital signs assessments	Starting about 24 hours before dosing and continued until about 7-14 days after last dose	Yes
Primary	Central nervous system safety assessments after single and multiple ascending dose administration at baseline and repeatedly until study completion	This safety outcome combines the measure of a set of central nervous system safety parameters extracted from EEGs and neurological examinations	Starting about 24 hours before dosing and continued until about 7-14 days after last dose	Yes
Primary	Ocular safety assessments after single and multiple ascending dose administration at baseline and repeatedly until study completion	This safety outcome combined the measure of a set of ocular parameters including best corrected visual acuity and other parameters assessed by the mean of slit lamp biomicroscopy and dilated ophthalmoscopy examinations and by optical coherence tomography and electroretinography	Starting about 24 hours before dosing and continued until about 7-14 days after last dose	Yes
Primary	General safety assessments after single and multiple ascending dose administration at baseline and repeatedly until study completion	This general safety outcome combines the measure of blood laboratory parameters and the outcome of physical examinations	Starting about 24 hours before dosing and continued until about 7-14 days after last dose	Yes
Secondary	Pharmacokinetics (PK) of LML134: time to reach the maximum concentration after a single drug administration (Tmax) in Part 1 and in Part 3	Serum samples will be collected on Day 1: 1hr predose; 0,25h; 0,5h; 1h; 1,5h; 2h; 3h; 4h; 6h; 8h; 12h; 16h post dose, on Day 2: 24h and 36h post dose, on Day 3: 48h and 60h post dose and on Day 4: 72h post dose. This outcome measure shows the mean of all subject values resulting from each time point specified above, in Parts 1 and 3.; In Part 3, the outcome measure is done once without food intake and once after the intake of a high fat breakfast (in 2 different periods). Both outcomes (with and without breakfast intake) will be compared to assess the effect of a high fast breakfast on LML134 Tmax	Starting 1hour prior to dosing on Day 1 and until 72 hours after dosing (Day 4)	No
Secondary	PK of LML134: Observed maximum serum concentration following single drug administration (Cmax) in Part 1 and Part 3	Serum samples will be collected on Day 1: 1hr predose; 0,25h; 0,5h; 1h; 1,5h; 2h; 3h; 4h; 6h; 8h; 12h; 16h post dose, on Day 2: 24h and 36h post dose, on Day 3: 48h and 60h post dose and on Day 4: 72h post dose. This outcome measure shows the mean of all subject values resulting from each time point specified above, in Parts 1 and 3.; In Part 3, the outcome measure is done once without food intake and once after the intake of a high fat breakfast (in 2 different periods). Both outcomes (with and without breakfast intake) will be compared to assess the effect of a high fast breakfast on LML134 Cmax.	Starting 1hour prior to dosing on Day 1 and until 72 hours after dosing (Day 4)	No
Secondary	PK of LML134: Area under the serum concentration-time curve from time zero to the time of last quantifiable concentration (AUClast) in Part 1 and Part 3	Serum samples will be collected on Day 1: 1hr predose; 0,25h; 0,5h; 1h; 1,5h; 2h; 3h; 4h; 6h; 8h; 12h; 16h post dose, on Day 2: 24h and 36h post dose, on Day 3: 48h and 60h post dose and on Day 4: 72h post dose. This outcome measure shows the mean of all subject values resulting from each time point specified above, in Parts 1 and 3. In Part 3, the outcome measure is done once without food intake and once after the intake of a high fat breakfast (in 2 different periods). Both outcomes (with and without breakfast intake) will be compared to assess the effect of a high fast breakfast on LML134 AUClast.	Starting 1hour prior to dosing on Day 1 and until 72 hours after dosing (Day 4)	No
Secondary	PK of LML134: time to reach the maximum concentration after the first drug administration (Tmax) in Part 2	Serum samples will be collected on Day 1: 1hr predose; 0,25h; 0,5h; 1h; 1,5h; 2h; 3h; 4h; 6h; 8h; 12h; 16h post dose and on Day 2: 24h post dose. This outcome measure shows the mean of all subject values resulting from each time point specified above.	Starting 1hour prior the first dose administration (Day 1) until 24hr after the first dose administration on Day 2	No
Secondary	PK of LML134: time to reach the maximum concentration after the last drug administration (Tmax) in Part 2	Serum samples will be collected on Day 1: 1hr predose; 0,25h; 0,5h; 1h; 1,5h; 2h; 3h; 4h; 6h; 8h; 12h; 16h post dose, on Day 2: 24h post dose, on Day 3: 1hr prior the second dose administration, on Days 4, 5, 6, 8, 10, 12, 13, 14: 1hr prior dosing, on Day 15 (last time the drug is administered): 1hr predose; 0,25h; 0,5h; 1h; 1,5h; 2h; 3h; 4h; 6h; 8h; 12h; 16h post dose, on Day 16: 24h post dose and Day 17: 48h post dose. This outcome measure shows the mean of all subject values resulting from each time point specified above.	Starting 1hour prior the first dose administration (Day 1) until 48hour after the last dose administration (Day 17)	No
Secondary	PK of LML134: Observed maximum serum concentration following the first drug administration (Cmax) in Part 2	Serum samples will be collected on Day 1: 1hr predose; 0,25h; 0,5h; 1h; 1,5h; 2h; 3h; 4h; 6h; 8h; 12h; 16h post dose and on Day 2: 24h post dose. This outcome measure shows the mean of all subject values resulting from each time point specified above.	Starting 1hour prior the first dose administration (Day 1) until 24hr after the first dose administration on Day 2	No
Secondary	PK of LML134: Observed maximum serum concentration following drug administration at steady state (Cmax,ss) in Part 2	Serum samples will be collected on Day 1: 1hr predose; 0,25h; 0,5h; 1h; 1,5h; 2h; 3h; 4h; 6h; 8h; 12h; 16h post dose, on Day 2: 24h post dose, on Day 3: 1hr prior the second dose administration, on Days 4, 5, 6, 8, 10, 12, 13, 14: 1hr prior dosing, on Day 15 (last time the drug is administered): 1hr predose; 0,25h; 0,5h; 1h; 1,5h; 2h; 3h; 4h; 6h; 8h; 12h; 16h post dose, on Day 16: 24h post dose and Day 17: 48h post dose. This outcome measure shows the mean of all subject values resulting from each time point specified above.	Starting 1hour prior the first dose administration (Day 1) until 48hour after the last dose administration (Day 17)	No
Secondary	PK of LML134: Area under the serum concentration-time curve from time zero to the time of last quantifiable concentration (AUClast) after the first dose administration in Part 2	Serum samples will be collected on Day 1: 1hr predose; 0,25h; 0,5h; 1h; 1,5h; 2h; 3h; 4h; 6h; 8h; 12h; 16h post dose and on Day 2: 24h post dose. This outcome measure shows the mean of all subject values resulting from each time point specified above.	Starting 1hour prior the first dose administration (Day 1) until 24hr after the first dose administration on Day 2	No
Secondary	PK of LML134: The area under the serum concentration-time curve from time zero to the end of the dosing interval tau at steady state (AUCtau,ss) in Part 2	Serum samples will be collected on Day 1: 1hr predose; 0,25h; 0,5h; 1h; 1,5h; 2h; 3h; 4h; 6h; 8h; 12h; 16h post dose, on Day 2: 24h post dose, on Day 3: 1hr prior the second dose administration, on Days 4, 5, 6, 8, 10, 12, 13, 14: 1hr prior dosing, on Day 15 (last time the drug is administered): 1hr predose; 0,25h; 0,5h; 1h; 1,5h; 2h; 3h; 4h; 6h; 8h; 12h; 16h post dose, on Day 16: 24h post dose and Day 17: 48h post dose. This outcome measure shows the mean of all subject values resulting from each time point specified above.	Starting 1hour prior the first dose administration (Day 1) until 48hour after the last dose administration (Day 17)	No
Secondary	PK of LML134: The average steady state serum concentration during multiple dosing (Cav,ss) in Part 2	Serum samples will be collected on Day 1: 1hr predose; 0,25h; 0,5h; 1h; 1,5h; 2h; 3h; 4h; 6h; 8h; 12h; 16h post dose, on Day 2: 24h post dose, on Day 3: 1hr prior the second dose administration, on Days 4, 5, 6, 8, 10, 12, 13, 14: 1hr prior dosing, on Day 15 (last time the drug is administered): 1hr predose; 0,25h; 0,5h; 1h; 1,5h; 2h; 3h; 4h; 6h; 8h; 12h; 16h post dose, on Day 16: 24h post dose and Day 17: 48h post dose. This outcome measure shows the mean of all subject values resulting from each time point specified above.	Starting 1hour prior the first dose administration (Day 1) until 48hour after the last dose administration (Day 17)	No
Secondary	PK of LML134: The effective half-life based on drug accumulation at steady state (T1/2,acc) in Part 2	Serum samples will be collected on Day 1: 1hr predose; 0,25h; 0,5h; 1h; 1,5h; 2h; 3h; 4h; 6h; 8h; 12h; 16h post dose, on Day 2: 24h post dose, on Day 3: 1hr prior the second dose administration, on Days 4, 5, 6, 8, 10, 12, 13, 14: 1hr prior dosing, on Day 15 (last time the drug is administered): 1hr predose; 0,25h; 0,5h; 1h; 1,5h; 2h; 3h; 4h; 6h; 8h; 12h; 16h post dose, on Day 16: 24h post dose and Day 17: 48h post dose. This outcome measure shows the mean of all subject values resulting from each time point specified above.	Starting 1hour prior the first dose administration (Day 1) until 48hour after the last dose administration (Day 17)	No
Secondary	PK of LML134: The accumulation ratio (Racc) in Part 2	Serum samples will be collected on Day 1: 1hr predose; 0,25h; 0,5h; 1h; 1,5h; 2h; 3h; 4h; 6h; 8h; 12h; 16h post dose, on Day 2: 24h post dose, on Day 3: 1hr prior the second dose administration, on Days 4, 5, 6, 8, 10, 12, 13, 14: 1hr prior dosing, on Day 15 (last time the drug is administered): 1hr predose; 0,25h; 0,5h; 1h; 1,5h; 2h; 3h; 4h; 6h; 8h; 12h; 16h post dose, on Day 16: 24h post dose and Day 17: 48h post dose. This outcome measure shows the mean of all subject values resulting from each time point specified above.	Starting 1hour prior the first dose administration (Day 1) until 48hour after the last dose administration (Day 17)	No