Phase 1 Study of Safety, Tolerability and Pharmacokinetics of SPR994

NCT03395249 | Completed Phase 1 DMC

• 1 other identifier: SPR994-101
• Study Type: interventional
• Target: 124
• Locations: 1 country
• Sites: 1

Brief Summary

This is a double-blind, placebo-controlled, ascending dose, multi-cohort trial. The study will be conducted in 2 parts: a single ascending dose (SAD) part, followed by a multiple ascending dose (MAD) part. In SAD, all subjects will receive 1 dose of SPR994 (100, 300, 600 or 900 mg) or placebo, except for subjects enrolled in food effect cohorts in which subjects will receive one dose following a 10 hour fast and a second dose in the fed state following a minimum 5 days washout period. There is a single, optional, open-label control cohort that may enroll, in which all 8 subjects will receive Orapenem® (tebipenem pivoxil fine granules). In MAD, subjects will receive multiple doses of SPR994 (300 or 600 mg) or placebo for 14 consecutive days at either BID or TID dosing. In both parts, cohorts will be exposed to increasing doses of SPR994 with various extended release formulations.

Conditions

Healthy Volunteers

Keywords

safety; tolerability; pharmacokinetics; SPR994

Outcome Measures

Primary Outcomes (10)

• Safety measures: adverse events

  The incidence and severity of AEs

  SAD: 1 to 7 days or 1 to 13 (food effect cohort); MAD 1 to 20 days

• Safety measures: concomitant medications

  The type and frequency of medications used

  SAD: 1 to 7 days or 1 to 13 (food effect cohort); MAD: 1 to 20 days

• Safety measures: physical examination

  Change from baseline to end of study visit

  SAD: -1 to 7 days or -1 to 13 (food effect cohort); MAD: -1 to 20 days

• Safety measures: weight

  Change from baseline to end of study visit

  SAD: -1 to 7 days or -1 to 13 (food effect cohort); MAD: -1 to 20 days

• Safety measures: pulse rate

  Change from baseline to end of study visit

  SAD: -1 to 7 days or -1 to 13 (food effect cohort); MAD: -1 to 20 days

• Safety measures: ECG

  Change from baseline to end of study visit

  SAD: -1 to 7 days or -1 to 13 (food effect cohort); MAD: -1 to 20 days

• Safety measures: clinical laboratory testing

  Change from baseline to end of study visit

  SAD: -1 to 7 days or -1 to 13 (food effect cohort); MAD: -1 to 20 days

• Safety measures: respiratory rate

  Change from baseline to end of study visit

  SAD: -1 to 7 days or -1 to 13 (food effect cohort); MAD: -1 to 20 days

• Safety measures: blood pressure

  Change from baseline to end of study visit

  SAD: -1 to 7 days or -1 to 13 (food effect cohort); MAD: -1 to 20 days

• Safety measures: body temperature

  Change from baseline to end of study visit

  SAD: -1 to 7 days or -1 to 13 (food effect cohort); MAD: -1 to 20 days

Secondary Outcomes (10)

• Pharmacokinetics: Time to maximum concentration (Tmax)

  SAD: Day 1 to Day 3 and Day 7 to 9 (Food Effect); MAD Day 1 to 16

• Pharmacokinetics: Maximum concentration (Cmax)

  SAD: Day 1 to Day 3 and Day 7 to 9 (Food Effect); MAD Day 1 to 16

• Pharmacokinetics: Area under the concentration-time curve from time 0 to last measurable time-point (AUC0-t)

  SAD: Day 1 to Day 3 and Day 7 to 9 (food effect); MAD Day 1 to 16

• Pharmacokinetics: Area under the concentration-time curve from time 0 to infinity (AUC0-inf)

  SAD: Day 1 to Day 3 and Day 7 to 9 (food effect); MAD Day 1 to 16

• Pharmacokinetics: Terminal Elimination Rate Constant (kel)

  SAD: Day 1 to Day 3 and Day 7 to 9 (food effect); MAD Day 1 to 16

Study Arms (3)

SPR994, FI, F2, F3, F4 Oral Tablets

EXPERIMENTAL

SPR994 is active against multidrug-resistant Gram-negative and Gram-positive pathogens that cause serious and life-threatening infections, including extended spectrum beta-lactamase (ESBL) producers as well as strains resistant to levofloxacin and trimethoprim/sulfamethoxazole. SPR994 is administered in tablet form orally. Up to five different time released formulations of SPR994 will be studied in this protocol at 100 mg, 300 mg, 600 mg and 900 mg dosages. SAD Cohorts: One dose (two for food effect cohort) MAD Cohorts: Twenty-seven (27) doses administered twice daily (BID) over a period of 14 days or forty doses administered three times daily (TID) over period of 14 days

Drug: SPR994

Placebo Oral Tablet

PLACEBO COMPARATOR

Placebo tablets (100, 300, and 600 mg) are pressed from a single placebo blend consisting of the same inactive ingredients; the active pharmaceutical ingredient (API) is replaced by Mannitol 200SD. SAD Cohorts: One dose (two for food effect cohort) MAD Cohorts: Twenty-seven (27) doses administered BID over a period of 14 days or forty doses administered TID over a period of 14 days

Drug: Placebo Oral Tablet

Optional Orapenem Open-Label Control

OTHER

A single, optional, open-label, control cohort that may enroll, in which all 8 subjects receive Orapenem. SAD Cohort: One dose under fasted conditions and one dose under fed conditions.

Drug: Orapenem®

Interventions

SPR994 DRUG

SAD: Double-blind dosing will occur in all SAD Cohorts except for Cohort 12. In each cohort, six subjects will receive one of five different timed release formulations of SPR994 and 2 subjects will receive placebo. Subjects in SAD Cohorts 2, 3, 6, 16 and 17 will receive a single dose following a 10-h fast. Subjects in SAD Cohorts 1, 8-15 will receive one dose of SPR994 or placebo following a 10-h fast on Day 1 and a second dose following consumption of a standardized meal on Day 7. The dose escalation steps may be altered following review of the safety data of each cohort. MAD: Double-blind dosing will occur in all MAD Cohorts. Subjects will receive multiple doses of an optimal timed release formulation of SPR994 in MAD Cohort 4 (300 mg) and Cohort 5 (600 mg) or placebo for 14 consecutive days at either BID or TID dosing beginning on Day 1.

Also known as: SPR994 Oral Tablet

SPR994, FI, F2, F3, F4 Oral Tablets

Placebo Oral Tablet DRUG

Mannitol 200SD SAD: Two subjects in each cohort will receive matching placebo. MAD: Two participants in each cohort will receive matching placebo.

Also known as: Placebo

Placebo Oral Tablet

Orapenem® DRUG

Tebipenem pivoxil granules

Also known as: Orapenem® fine granules

Optional Orapenem Open-Label Control

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Healthy adult males and/or females (of non-childbearing potential), 18 to 55 years of age (inclusive) at the time of screening;
• Body mass index ≥ 18.5 and ≤ 29.9 (kg/m2) and 55.0 and 100.0 kg (inclusive) for all cohorts;
• Medically healthy without clinically significant (CS) abnormalities at the screening visit or Day -1, including:
• Physical examination, vital signs including temperature, heart rate, respiratory rate, and blood pressure;
• Triplicate electrocardiograms (ECGs) taken at least 1 minute apart with QT wave corrected for heart rate (HR) using Fridericia's method (QTcF) interval duration less than 450 msec obtained as an average from the triplicate screening and pre-dose Day 1 ECGs after at least 5 min in a semi-supine quiet rest;
• Haemoglobin \> 12.5, haematocrit 37%, white blood cell (WBC) count \> 3.5, or platelet count equal to or greater than the lower limit of normal range of the reference laboratory (may be confirmed upon repeat analysis);
• Creatinine, blood urea nitrogen (BUN), equal to or less than the upper limit of normal; alanine aminotransferase (ALT) and aspartate aminotransferase (AST) equal to or \< 1.5 times the upper limit of normal for the reference laboratory and confirmed on repeat analysis; results of all other clinical chemistry and urine analytes without any CS abnormality.
• Discussion between the PI and the Sponsor Medical Monitor is encouraged regarding any abnormal laboratory value that is outside of the normal range during the pre-dose period.
• Be non-smokers (including tobacco, e-cigarettes or marijuana) for at least 1 month prior to participation in the study;
• Willing and able to provide written informed consent;
• Be willing and able to comply with all study assessments and adhere to the protocol schedule;
• Have suitable venous access for blood sampling;
• If female, be of non-childbearing potential (e.g. post-menopausal as demonstrated by follicle stimulating hormone or surgical sterilization i.e., tubal ligation or hysterectomy). Provision of documentation is not required for female sterilization, verbal confirmation is adequate;
• If male, a willingness not to donate sperm and if engaging in sexual intercourse with a female partner who could become pregnant, a willingness to use a condom in addition to having the female partner use a highly effective method of birth control (such as an intrauterine device, diaphragm, oral contraceptives, injectable progesterone, subdermal implants, or a tubal ligation). This criterion applies to males (and/or female partners) who are surgically sterile and must be followed from the time of first study drug administration until 30 days after the final administration of study drug.

You may not qualify if:

• History or presence of significant cardiovascular, pulmonary, hepatic, renal, haematological, gastrointestinal, endocrine, immunologic, dermatologic or neurological disease, including any acute illness or surgery within the past 3 months determined by the PI to be clinically relevant;
• History of known or suspected Clostridium difficile infection;
• History of seizure disorders, except for a single febrile seizure in childhood;
• Positive urine drug/alcohol testing at screening or Day -1;
• Positive testing for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis C antibodies (HCV);
• History of substance abuse or alcohol abuse (defined as greater than 2 standard drinks on average each and every day, where 1 standard drink is defined as containing 10 g of alcohol and is equivalent to 1 can or stubby of mid-strength beer, 30 ml nip spirits, or 100 ml wine) within the previous 5 years;
• Use of any prescription medication or any over-the-counter medication, including herbal products and vitamins within 7 days prior to randomization;
• Documented hypersensitivity reaction or anaphylaxis to any medication;
• Donation of blood or plasma within 30 days prior to randomization, or loss of whole blood of more than 500 mL within 30 days prior to randomization, or receipt of a blood transfusion within 1 year of study enrollment;
• Participation in another investigational clinical trial within 30 days prior to Day 1;
• Any other condition or prior therapy, which, in the opinion of the PI, would make the volunteer unsuitable for this study, including unable to cooperate fully with the requirements of the study protocol or likely to be non-compliant with any study requirements.

Sponsors & Collaborators

• Spero Therapeutics: lead
• CPR Pharma Services Pty Ltd, Australia: collaborator

Study Sites (1)

Scientia Clinical Research Ltd

Randwick, New South Wales, 2031, Australia

Location

Related Publications (1)

• Eckburg PB, Jain A, Walpole S, Moore G, Utley L, Manyak E, Dane A, Melnick D. Safety, Pharmacokinetics, and Food Effect of Tebipenem Pivoxil Hydrobromide after Single and Multiple Ascending Oral Doses in Healthy Adult Subjects. Antimicrob Agents Chemother. 2019 Aug 23;63(9):e00618-19. doi: 10.1128/AAC.00618-19. Print 2019 Sep.

  PMID: 31262768 DERIVED

MeSH Terms

Interventions

tebipenem

Study Officials

• Charlotte Lemech, FRACP, MD

  Scientia Clinical Research Limited

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Subjects will be randomized in a 3:1 ratio of SPR994 to placebo. Study drug tablets, both active and placebo, are the same shape, weight and size. Those blinded to study drug assignment include the sponsor, the PI, clinical study personnel participating in subjects' care or clinical evaluations, and the subjects. Those unblinded to study drug assignment include the statisticians preparing the randomisation, pharmacy personnel, the unblinded study monitor, the bioanalytical laboratory, and the pharmacokineticist performing interim PK analysis.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Randomized, double-blind, placebo-controlled, combined single and multiple ascending dose (SAD and MAD) trial

Study Record Dates

• First Submitted: October 19, 2017
• First Posted: January 10, 2018
• Study Start: October 20, 2017
• Primary Completion: August 2, 2018
• Study Completion: August 2, 2018
• Last Updated: August 28, 2018

Record last verified: 2018-03

Locations

AU (1)