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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT03395249




Registration number
NCT03395249
Ethics application status
Date submitted
19/10/2017
Date registered
10/01/2018
Date last updated
28/08/2018

Titles & IDs
Public title
Phase 1 Study of Safety, Tolerability and Pharmacokinetics of SPR994
Scientific title
A Two-part, Double-blind, Placebo-controlled, Phase I Study of the Safety, Tolerability and Pharmacokinetics of SPR994 Following Single and Multiple Ascending Doses of SPR994 Administered Orally in Healthy Volunteers
Secondary ID [1] 0 0
SPR994-101
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Healthy Volunteers 0 0
Condition category
Condition code

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - SPR994
Treatment: Drugs - Placebo Oral Tablet
Treatment: Drugs - Orapenem®

Experimental: SPR994, FI, F2, F3, F4 Oral Tablets - 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

Placebo comparator: Placebo Oral Tablet - 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

Other: Optional Orapenem Open-Label Control - 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.


Treatment: Drugs: SPR994
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.

Treatment: Drugs: Placebo Oral Tablet
Mannitol 200SD SAD: Two subjects in each cohort will receive matching placebo. MAD: Two participants in each cohort will receive matching placebo.

Treatment: Drugs: Orapenem®
Tebipenem pivoxil granules
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Safety measures: adverse events
Timepoint [1] 0 0
SAD: 1 to 7 days or 1 to 13 (food effect cohort); MAD 1 to 20 days
Primary outcome [2] 0 0
Safety measures: concomitant medications
Timepoint [2] 0 0
SAD: 1 to 7 days or 1 to 13 (food effect cohort); MAD: 1 to 20 days
Primary outcome [3] 0 0
Safety measures: physical examination
Timepoint [3] 0 0
SAD: -1 to 7 days or -1 to 13 (food effect cohort); MAD: -1 to 20 days
Primary outcome [4] 0 0
Safety measures: weight
Timepoint [4] 0 0
SAD: -1 to 7 days or -1 to 13 (food effect cohort); MAD: -1 to 20 days
Primary outcome [5] 0 0
Safety measures: pulse rate
Timepoint [5] 0 0
SAD: -1 to 7 days or -1 to 13 (food effect cohort); MAD: -1 to 20 days
Primary outcome [6] 0 0
Safety measures: ECG
Timepoint [6] 0 0
SAD: -1 to 7 days or -1 to 13 (food effect cohort); MAD: -1 to 20 days
Primary outcome [7] 0 0
Safety measures: clinical laboratory testing
Timepoint [7] 0 0
SAD: -1 to 7 days or -1 to 13 (food effect cohort); MAD: -1 to 20 days
Primary outcome [8] 0 0
Safety measures: respiratory rate
Timepoint [8] 0 0
SAD: -1 to 7 days or -1 to 13 (food effect cohort); MAD: -1 to 20 days
Primary outcome [9] 0 0
Safety measures: blood pressure
Timepoint [9] 0 0
SAD: -1 to 7 days or -1 to 13 (food effect cohort); MAD: -1 to 20 days
Primary outcome [10] 0 0
Safety measures: body temperature
Timepoint [10] 0 0
SAD: -1 to 7 days or -1 to 13 (food effect cohort); MAD: -1 to 20 days
Secondary outcome [1] 0 0
Pharmacokinetics: Time to maximum concentration (Tmax)
Timepoint [1] 0 0
SAD: Day 1 to Day 3 and Day 7 to 9 (Food Effect); MAD Day 1 to 16
Secondary outcome [2] 0 0
Pharmacokinetics: Maximum concentration (Cmax)
Timepoint [2] 0 0
SAD: Day 1 to Day 3 and Day 7 to 9 (Food Effect); MAD Day 1 to 16
Secondary outcome [3] 0 0
Pharmacokinetics: Area under the concentration-time curve from time 0 to last measurable time-point (AUC0-t)
Timepoint [3] 0 0
SAD: Day 1 to Day 3 and Day 7 to 9 (food effect); MAD Day 1 to 16
Secondary outcome [4] 0 0
Pharmacokinetics: Area under the concentration-time curve from time 0 to infinity (AUC0-inf)
Timepoint [4] 0 0
SAD: Day 1 to Day 3 and Day 7 to 9 (food effect); MAD Day 1 to 16
Secondary outcome [5] 0 0
Pharmacokinetics: Terminal Elimination Rate Constant (kel)
Timepoint [5] 0 0
SAD: Day 1 to Day 3 and Day 7 to 9 (food effect); MAD Day 1 to 16
Secondary outcome [6] 0 0
Pharmacokinetics: Terminal half-life (t1/2)
Timepoint [6] 0 0
SAD: Day 1 to Day 3 and Day 7 to 9 (food effect); MAD Day 1 to 16
Secondary outcome [7] 0 0
Pharmacokinetics: Terminal clearance (CL/F)
Timepoint [7] 0 0
SAD: Day 1 to Day 3 and Day 7 to 9 (food effect); MAD Day 1 to 16
Secondary outcome [8] 0 0
Pharmacokinetics: Volume of distribution
Timepoint [8] 0 0
SAD: Day 1 to Day 3 and Day 7 to 9 (food effect); MAD Day 1 to 16
Secondary outcome [9] 0 0
Pharmacokinetics: Area under the concentration-time curve from 0 to 12 hours from the start of first dose (AUC0-12h)
Timepoint [9] 0 0
SAD: Day 1 to Day 3 and Day 7 to 9 (food effect); MAD Day 1 to 16
Secondary outcome [10] 0 0
Pharmacokinetics: SPR994 excreted in urine in each collection interval
Timepoint [10] 0 0
SAD: Days 1-2 and 7-8 (food effect cohorts). MAD: Day 1-2 and 14-15.

Eligibility
Key inclusion criteria
* 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:

1. Physical examination, vital signs including temperature, heart rate, respiratory rate, and blood pressure;
2. 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;
3. 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);
4. 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.
Minimum age
18 Years
Maximum age
55 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
* 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled 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
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
20/10/2017
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
2/08/2018
Sample size
Target
Accrual to date
Final
124
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 0 0
Scientia Clinical Research Ltd - Randwick
Recruitment postcode(s) [1] 0 0
2031 - Randwick

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Spero Therapeutics
Address
Country
Other collaborator category [1] 0 0
Commercial sector/industry
Name [1] 0 0
CPR Pharma Services Pty Ltd, Australia
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/study/NCT03395249
Trial related presentations / publications
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.
Public notes

Contacts
Principal investigator
Name 0 0
Charlotte Lemech, FRACP, MD
Address 0 0
Scientia Clinical Research Limited
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/study/NCT03395249