Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of GS-248

NCT04036227 | Completed Phase 1 Results

• 1 other identifier: GS-1001
• Study Type: interventional
• Target: 72
• Locations: 1 country
• Sites: 1

Brief Summary

This is a First in Human (FIH), double-blinded, parallel-group, randomised, placebo-controlled study designed to evaluate the safety, tolerability, PK and PD of single and multiple ascending oral doses of GS-248 in healthy subjects.

Conditions

Healthy

Outcome Measures

Primary Outcomes (5)

• Number of Treatment Related Adverse Events

  AEs were assessed as 'unlikely', 'possibly' or 'probably' related to the IMP. 'Possibly' and 'probably' were categorized as treatment related.

  AEs were collected from the start of IMP administration until the end-of-study visit of each part, an average of 10 days in Part 1 (SAD) and 20 days in Part 2 (MAD).

• Clinically Significant Changes in ECG

  Single 12-lead ECG was recorded in supine position after 10 minutes of rest using an ECG machine. Heart rate and PQ/PR, QRS, QT and QTcF intervals were recorded. Ambulatory ECG telemetry was used for cardiac surveillance up to 24 h after IMP administration in the SAD part of the study.

  12-lead ECG was measured at pre-defined timepoints from the screening visit until the end-of-study visit, an average of 10 days in Part I (SAD) and 20 days in Part II (MAD).

• Clinically Significant Changes in Vital Signs

  Systolic and diastolic blood pressure and pulse were measured in supine position after 10 minutes of rest. Body temperature was measured orally using a digital thermometer.

  Vital signs was checked at pre-defined timepoints from the screening visit until the end-of-study visit, an average of 10 days in Part 1 (SAD) and 20 days in Part 2 (MAD).

• Clinically Significant Changes in Safety Laboratory Parameters

  Blood samples for analysis of clinical chemistry, haematology and coagulation parameters.

  Blood samples were collected at pre-defined timepoints from the screening visit until the end-of-study visit, an average of 10 days in Part I (SAD) and 20 days in Part II (MAD).

• Clinically Significant Changes in Physical Examination

  A complete physical examination included assessments of the head, eyes, ears, nose, throat, skin, thyroid, neurological, lungs, cardiovascular, abdomen (liver and spleen), lymph nodes and extremities.

  Physical examination was performed at pre-defined timepoints from the screening visit until the end-of- study visit, an average of 10 days in Part I (SAD) and 20 days in Part II (MAD).

Secondary Outcomes (9)

• Cmax:

  SAD: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48 hours post-dose; MAD Day 1-3 (first dose) and Day 10-12 (last dose): pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48 hours post-dose.

• Tmax:

  SAD: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48 hours post-dose; MAD: Day 1-3 (first dose) Day 10-12 (last dose): pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48 hours post-dose.

• T½:

  SAD: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48 hours post-dose); MAD: Day 1-3 and Day 10-12: pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48 hours post-dose.

• AUC0-t:

  SAD: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48 hours post-dose); MAD: Day 1-3 and Day 10-12: pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48 hours post-dose.

• AUC 0-inf

  SAD: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48 hours post-dose

Other Outcomes (1)

• mPGES-1 Activity

  At 24h after first dose Day 1 and at 24 hours after last dose Day 10.

Study Arms (2)

GS-248

EXPERIMENTAL

Part I (SAD): Single doses of 1 mg, 5 mg, 25 mg, 75 mg, 225 mg and 450 mg (planned doses) Part II (MAD): Multiple ascending doses for 10 days in four cohorts with planned doses of 25 mg, 75 mg, 225 mg and 450 mg. The doses will be finally selected based on results from Part I.

Drug: GS-248

Placebo

PLACEBO COMPARATOR

Matching placebo oral solution

Drug: Placebo

Interventions

GS-248 DRUG

GS-248 oral solution

GS-248

Placebo DRUG

Placebo oral solution with the same composition to match active drug

Placebo

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Willing and able to give written informed consent for participation in the study.
• Male and female healthy subjects aged 18-70 years inclusive (Part I \[SAD\]) and 40-75 years inclusive (Part II \[MAD\])
• Women of child bearing potential must practice abstinence or must agree to use a highly effective method of contraception with a failure rate of \< 1% to prevent pregnancy from at least 4 weeks prior to dose to 4 weeks after last dose. Their male partner must agree to use a condom during the same time frame. Women of non-childbearing potential are defined as pre-menopausal females who are sterilised or post-menopausal defined as 12 months of amenorrhea.
• Male subjects must be willing to use condom or be vasectomised or practice sexual abstinence. Their female partner of child-bearing potential must use contraceptive methods with a failure rate of \< 1% to prevent pregnancy (see above).
• Body mass index (BMI) ≥ 19 and ≤ 30 kg/m2.
• Subjects must be in good health as determined by medical history, physical examination, vital signs, 12-lead ECG and clinical laboratory assessments at the time of screening, as judged by the Investigator.

You may not qualify if:

• Known allergy to any components of the GS-248 formulation.
• Females who are breast feeding or plan to be pregnant.
• Positive serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin \[HCG\]) at screening and within 24 h prior to the first administration of Investigational Medicinal Product (IMP).
• Use of corticosteroids (inhaled and systemic), NSAIDs (including e.g. coxibs and aspirin), antacids, Proton pump inhibitors (PPIs) or any medication that changes gastric pH within 2 weeks prior to the (first) administration of IMP.
• Regular use of any prescribed or non-prescribed medication including analgesics, herbal remedies, vitamins and minerals within 2 weeks prior to the (first) administration of IMP, except hormonal contraception and occasional intake of paracetamol (maximum 2000 mg/day; and not exceeding 3000 mg/week) and nasal decongestants without cortisone, antihistamine or anticholinergics for a maximum of 10 days, at the discretion of the Investigator.
• Inherited or acquired disorders of platelet function, bleeding or coagulation.
• Presence of any clinically relevant acute or chronic disease that could interfere with the subject's safety during the clinical study or expose the subject to undue risk.
• After 10 minutes supine rest at the time of screening, any vital signs values outside the following ranges:
• Systolic blood pressure \<90 or \>140 mmHg, or
• Diastolic blood pressure \<50 or \>90 mmHg, or
• Pulse \<40 or \>90 bpm
• Any positive result on screening for serum hepatitis B surface antigen (HBsAg), hepatitis C virus antibodies (HCVAb) or human immunodeficiency virus (HIV) 1 and/or 2 antibodies at screening.
• Presence or history of drug and/or alcohol abuse and/or excessive intake of alcohol and/or history, or current use, of anabolic steroids, as judged by the Investigator.
• Any positive result for drug abuse and/or alcohol at screening or on admission to the unit prior to administration of the IMP.
• Participation in another clinical study with an experimental drug within 3 months before the administration of IMP.

Sponsors & Collaborators

• Gesynta Pharma AB: lead
• CTC Clinical Trial Consultants AB: collaborator

Study Sites (1)

CTC Clinical Trial Consultants AB

Uppsala, SE-75237, Sweden

Location

Limitations and Caveats

Part I=SAD was completed in full. Part II=MAD was completed after three of four cohorts. Reason: Systemic exposure of GS-248 was considered sufficiently high after 3 MAD cohorts. Part III= Systemic sclerosis patients was cancelled. Reason: Decision by Sponsor that performing this part would not add scientific value to the development programme for GS-248. Part IV=Celecoxib was completed in full. Only celecoxib given in this exploratory comparison and thus results excluded in result section.

Results Point of Contact

• Title: Charlotte Edenius
• Organization: Gesynta Pharma AB

ctg@gesynta.se

+46733864246

Study Officials

• Folke Sjöberg, MD

  CTC Clinical Trial Consultants AB

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: The study will be conducted in double-blind fashion and the allocation of treatments will not be disclosed until clean file has been declared and the database has been locked. GS-248 and the placebo are identical in appearance, taste and smell.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Part I (SAD) Within each cohort, subjects will be randomised in a 3:1 ratio to receive either GS 248 (n=6) or placebo (n=2) in a blinded fashion. Part II (MAD) Within each cohort, subjects will be randomised in a 3:1 ratio to receive GS-248 (n=6) or placebo (n=2) in a blinded fashion.

Study Record Dates

• First Submitted: July 23, 2019
• First Posted: July 29, 2019
• Study Start: July 3, 2019
• Primary Completion: December 20, 2019
• Study Completion: December 20, 2019
• Last Updated: October 11, 2023
• Results First Posted: September 8, 2023

Record last verified: 2022-05

Data Sharing

• IPD Sharing: Will not share

Locations

SE (1)