Healthy VolunteersPhase 1NCT03395249
Phase 1 Study of Safety, Tolerability and Pharmacokinetics of SPR994
A Phase 1 study testing SPR994 and Orapenem® in people with Healthy Volunteers, run by Spero Therapeutics at 1 site in Australia.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 55 yearsHealthy volunteers can take part
- Conditions the study is for
- Healthy Volunteers
- What is being tested?
- SPR994 and Orapenem®
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 124 participants
- Where
- 1 siteAustralia
- Study dates
- 20 Oct 2017to 2 Aug 2018
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 55 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- 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);
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- 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.
Who cannot join
- 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;
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- 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.
Trial locations and contacts
1 site in 1 country.
Australia1 site
Scientia Clinical Research Ltd
Randwick, New South Wales, 2031
About this study
Official 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
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.
Read the detailed description
This study is a randomized, double-blind, placebo-controlled, combined single and multiple ascending dose (SAD and MAD) trial. Up to one hundred fifty two (152) subjects aged 18-55, who fulfill the inclusion/exclusion criteria, may be enrolled in this study. Up to a total of 17 SAD and 2 MAD cohorts of eight subjects each will be examined. Subjects in each cohort will be randomized 3:1 to receive SPR994 at doses ranging from 100 mg to 900 mg or placebo in various immediate and timed release formulations. One SAD control cohort, Cohort 12, may be enrolled in which eight subjects will receive a single dose of Orapenem® at 300 mg in a fed and fasted state. Dosing is complete in SAD Cohorts 1-3, 6 and 7. Subjects in Cohorts 1-3 received a single dose of SPR994 and subjects in food effect Cohorts 6 and 7 each received 2 doses. Subjects enrolled in SAD Cohorts 8 and beyond will receive a single dose of SPR994 or placebo in a fasted state and a second dose following a standardized meal to investigate food effect on the pharmacokinetics of SPR994 and TBPM. SAD Cohorts 8 through 10 may run in a staggered or concurrent manner before enrollment of further cohorts. Blinded pharmacokinetic data will be reviewed at the conclusion of Cohort 10 (300 mg fasted \& fed). Should the PK be optimized in one of the various time released formulations, the Sponsor may decide to proceed to enrollment of the 600 mg Cohorts using the optimal formulation; other timed release formulations may also be explored at 300 mg dose in a staggered or concurrent manner until an optimal formulation(s) is identified. When an optimal formulation(s) is identified, the 600 mg Cohorts may run in a staggered or concurrent manner. SAD Cohorts 16 (100 mg fasted) and 17 (900 mg fasted) may run prior to or in a staggered or concurrent manner with MAD Cohorts 4 (300 mg) and 5 (600 mg). During the MAD part of the study, subjects will receive 27 doses of SPR994 or placebo over a period of 14 days. Based on the observed PK of SPR994 in prior cohorts, the total number of doses may be increased to 40 doses of SPR994 or placebo administered TID over 14 days; only one dose will be administered on Day 14 to allow for PK sample collection In both SAD and MAD parts of the study, the Cohorts will be exposed to increasing doses of SPR994. Each part (SAD and MAD) of the study will consist of 3 periods: a screening period, a treatment period, and a follow-up period. The safety and tolerability of SPR994 will be assessed based on the types and frequency of adverse events (AEs) reported; concomitant medication usage; and changes from baseline in physical examination, weight, vital signs, ECG, and standard clinical laboratory tests. A Safety Management Group (SMG) will review the data of cohorts prior to escalating to the next dose level.
- Conditions
- Healthy Volunteers
- Being tested
- SPR994, Placebo Oral Tablet, Orapenem®
- Keywords
- safety, tolerability, pharmacokinetics, SPR994
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
SPR994Drug
Also called SPR994 Oral Tablet
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.
Placebo Oral TabletDrug
Also called Placebo
Mannitol 200SD SAD: Two subjects in each cohort will receive matching placebo. MAD: Two participants in each cohort will receive matching placebo.
Orapenem®Drug
Also called Orapenem® fine granules
Tebipenem pivoxil granules
| Study group | Role | What they receive |
|---|---|---|
| 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 Receives: 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 Receives: 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. Receives: Drug: Orapenem® |
What is being measured
The primary outcome is the main question the study is designed to answer.
Safety measures: adverse events
The incidence and severity of AEs
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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)
Plasma Sample Collection for PK Analysis:
SAD Cohorts 1 and 7: Days 1 and 7 (Food Effect Cohorts) at pre-dose and at 15, 30, 45 min and 1, 2, 4, 6, 8, 12, 24, and 48 h post-dose.
SAD Cohorts 2, 3, and 6: Day 1 at the same time-points as SAD Cohorts 1 and 7. SAD Cohorts 8 - 15: Days 1 and 7 (Food Effect Cohorts) at pre-dose and at 15, 30, 45 min and 1, 1.5, 2, 4, 6, 8, 12, 24, and 48 h post-dose.
SAD Cohorts 16 and 17: Day 1 at the same time-points as SAD Cohorts 8 - 15. MAD Cohorts 4 and 5: Day 1 at pre-dose and at 15, 30, 45 min and 1, 1.5, 2, 4, 6, 8, 12 h following start of the first dose (BID dosing) or pre-dose and at 15, 30, 45 min and 1, 1.5, 2, 4, 6 and 8 h following start of first dose and prior to second dose (TID dosing); Prior to the morning dose on Days 2, 3, 5, 7, 9, 11 and 13; Pre-dose, 15, 30, 45 min and 1, 1.5, 2, 4, 6, 8
Measured: SAD: Day 1 to Day 3 and Day 7 to 9 (Food Effect); MAD Day 1 to 16
Pharmacokinetics: Maximum concentration (Cmax)
Plasma Sample Collection for PK Analysis:
SAD Cohorts 1 and 7: Days 1 and 7 (Food Effect Cohorts) at pre-dose and at 15, 30, 45 min and 1, 2, 4, 6, 8, 12, 24, and 48 h post-dose.
SAD Cohorts 2, 3, and 6: Day 1 at the same time-points as SAD Cohorts 1 and 7. SAD Cohorts 8 - 15: Days 1 and 7 (Food Effect Cohorts) at pre-dose and at 15, 30, 45 min and 1, 1.5, 2, 4, 6, 8, 12, 24, and 48 h post-dose.
SAD Cohorts 16 and 17: Day 1 at the same time-points as SAD Cohorts 8 - 15. MAD Cohorts 4 and 5: Day 1 at pre-dose and at 15, 30, 45 min and 1, 1.5, 2, 4, 6, 8, 12 h following start of the first dose (BID dosing) or pre-dose and at 15, 30, 45 min and 1, 1.5, 2, 4, 6 and 8 h following start of first dose and prior to second dose (TID dosing); Prior to the morning dose on Days 2, 3, 5, 7, 9, 11 and 13; Pre-dose, 15, 30, 45 min and 1, 1.5, 2, 4, 6, 8
Measured: 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)
Plasma Sample Collection for PK Analysis:
SAD Cohorts 1 and 7: Days 1 and 7 (Food Effect Cohorts) at pre-dose and at 15, 30, 45 min and 1, 2, 4, 6, 8, 12, 24, and 48 h post-dose.
SAD Cohorts 2, 3, and 6: Day 1 at the same time-points as SAD Cohorts 1 and 7. SAD Cohorts 8 - 15: Days 1 and 7 (Food Effect Cohorts) at pre-dose and at 15, 30, 45 min and 1, 1.5, 2, 4, 6, 8, 12, 24, and 48 h post-dose.
SAD Cohorts 16 and 17: Day 1 at the same time-points as SAD Cohorts 8 - 15. MAD Cohorts 4 and 5: Day 1 at pre-dose and at 15, 30, 45 min and 1, 1.5, 2, 4, 6, 8, 12 h following start of the first dose (BID dosing) or pre-dose and at 15, 30, 45 min and 1, 1.5, 2, 4, 6 and 8 h following start of first dose and prior to second dose (TID dosing); Prior to the morning dose on Days 2, 3, 5, 7, 9, 11 and 13; Pre-dose, 15, 30, 45 min and 1, 1.5, 2, 4, 6, 8
Measured: 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)
Plasma Sample Collection for PK Analysis:
SAD Cohorts 1 and 7: Days 1 and 7 (Food Effect Cohorts) at pre-dose and at 15, 30, 45 min and 1, 2, 4, 6, 8, 12, 24, and 48 h post-dose.
SAD Cohorts 2, 3, and 6: Day 1 at the same time-points as SAD Cohorts 1 and 7. SAD Cohorts 8 - 15: Days 1 and 7 (Food Effect Cohorts) at pre-dose and at 15, 30, 45 min and 1, 1.5, 2, 4, 6, 8, 12, 24, and 48 h post-dose.
SAD Cohorts 16 and 17: Day 1 at the same time-points as SAD Cohorts 8 - 15. MAD Cohorts 4 and 5: Day 1 at pre-dose and at 15, 30, 45 min and 1, 1.5, 2, 4, 6, 8, 12 h following start of the first dose (BID dosing) or pre-dose and at 15, 30, 45 min and 1, 1.5, 2, 4, 6 and 8 h following start of first dose and prior to second dose (TID dosing); Prior to the morning dose on Days 2, 3, 5, 7, 9, 11 and 13; Pre-dose, 15, 30, 45 min and 1, 1.5, 2, 4, 6, 8
Measured: SAD: Day 1 to Day 3 and Day 7 to 9 (food effect); MAD Day 1 to 16
Pharmacokinetics: Terminal Elimination Rate Constant (kel)
Plasma Sample Collection for PK Analysis:
SAD Cohorts 1 and 7: Days 1 and 7 (Food Effect Cohorts) at pre-dose and at 15, 30, 45 min and 1, 2, 4, 6, 8, 12, 24, and 48 h post-dose.
SAD Cohorts 2, 3, and 6: Day 1 at the same time-points as SAD Cohorts 1 and 7. SAD Cohorts 8 - 15: Days 1 and 7 (Food Effect Cohorts) at pre-dose and at 15, 30, 45 min and 1, 1.5, 2, 4, 6, 8, 12, 24, and 48 h post-dose.
SAD Cohorts 16 and 17: Day 1 at the same time-points as SAD Cohorts 8 - 15. MAD Cohorts 4 and 5: Day 1 at pre-dose and at 15, 30, 45 min and 1, 1.5, 2, 4, 6, 8, 12 h following start of the first dose (BID dosing) or pre-dose and at 15, 30, 45 min and 1, 1.5, 2, 4, 6 and 8 h following start of first dose and prior to second dose (TID dosing); Prior to the morning dose on Days 2, 3, 5, 7, 9, 11 and 13; Pre-dose, 15, 30, 45 min and 1, 1.5, 2, 4, 6, 8
Measured: SAD: Day 1 to Day 3 and Day 7 to 9 (food effect); MAD Day 1 to 16
Pharmacokinetics: Terminal half-life (t1/2)
Plasma Sample Collection for PK Analysis:
SAD Cohorts 1 and 7: Days 1 and 7 (Food Effect Cohorts) at pre-dose and at 15, 30, 45 min and 1, 2, 4, 6, 8, 12, 24, and 48 h post-dose.
SAD Cohorts 2, 3, and 6: Day 1 at the same time-points as SAD Cohorts 1 and 7. SAD Cohorts 8 - 15: Days 1 and 7 (Food Effect Cohorts) at pre-dose and at 15, 30, 45 min and 1, 1.5, 2, 4, 6, 8, 12, 24, and 48 h post-dose.
SAD Cohorts 16 and 17: Day 1 at the same time-points as SAD Cohorts 8 - 15. MAD Cohorts 4 and 5: Day 1 at pre-dose and at 15, 30, 45 min and 1, 1.5, 2, 4, 6, 8, 12 h following start of the first dose (BID dosing) or pre-dose and at 15, 30, 45 min and 1, 1.5, 2, 4, 6 and 8 h following start of first dose and prior to second dose (TID dosing); Prior to the morning dose on Days 2, 3, 5, 7, 9, 11 and 13; Pre-dose, 15, 30, 45 min and 1, 1.5, 2, 4, 6, 8
Measured: SAD: Day 1 to Day 3 and Day 7 to 9 (food effect); MAD Day 1 to 16
Pharmacokinetics: Terminal clearance (CL/F)
Plasma Sample Collection for PK Analysis:
SAD Cohorts 1 and 7: Days 1 and 7 (Food Effect Cohorts) at pre-dose and at 15, 30, 45 min and 1, 2, 4, 6, 8, 12, 24, and 48 h post-dose.
SAD Cohorts 2, 3, and 6: Day 1 at the same time-points as SAD Cohorts 1 and 7. SAD Cohorts 8 - 15: Days 1 and 7 (Food Effect Cohorts) at pre-dose and at 15, 30, 45 min and 1, 1.5, 2, 4, 6, 8, 12, 24, and 48 h post-dose.
SAD Cohorts 16 and 17: Day 1 at the same time-points as SAD Cohorts 8 - 15. MAD Cohorts 4 and 5: Day 1 at pre-dose and at 15, 30, 45 min and 1, 1.5, 2, 4, 6, 8, 12 h following start of the first dose (BID dosing) or pre-dose and at 15, 30, 45 min and 1, 1.5, 2, 4, 6 and 8 h following start of first dose and prior to second dose (TID dosing); Prior to the morning dose on Days 2, 3, 5, 7, 9, 11 and 13; Pre-dose, 15, 30, 45 min and 1, 1.5, 2, 4, 6, 8
Measured: SAD: Day 1 to Day 3 and Day 7 to 9 (food effect); MAD Day 1 to 16
Pharmacokinetics: Volume of distribution
Plasma Sample Collection for PK Analysis:
SAD Cohorts 1 and 7: Days 1 and 7 (Food Effect Cohorts) at pre-dose and at 15, 30, 45 min and 1, 2, 4, 6, 8, 12, 24, and 48 h post-dose.
SAD Cohorts 2, 3, and 6: Day 1 at the same time-points as SAD Cohorts 1 and 7. SAD Cohorts 8 - 15: Days 1 and 7 (Food Effect Cohorts) at pre-dose and at 15, 30, 45 min and 1, 1.5, 2, 4, 6, 8, 12, 24, and 48 h post-dose.
SAD Cohorts 16 and 17: Day 1 at the same time-points as SAD Cohorts 8 - 15. MAD Cohorts 4 and 5: Day 1 at pre-dose and at 15, 30, 45 min and 1, 1.5, 2, 4, 6, 8, 12 h following start of the first dose (BID dosing) or pre-dose and at 15, 30, 45 min and 1, 1.5, 2, 4, 6 and 8 h following start of first dose and prior to second dose (TID dosing); Prior to the morning dose on Days 2, 3, 5, 7, 9, 11 and 13; Pre-dose, 15, 30, 45 min and 1, 1.5, 2, 4, 6, 8
Measured: 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 0 to 12 hours from the start of first dose (AUC0-12h)
Plasma Sample Collection for PK Analysis:
SAD Cohorts 1 and 7: Days 1 and 7 (Food Effect Cohorts) at pre-dose and at 15, 30, 45 min and 1, 2, 4, 6, 8, 12, 24, and 48 h post-dose.
SAD Cohorts 2, 3, and 6: Day 1 at the same time-points as SAD Cohorts 1 and 7. SAD Cohorts 8 - 15: Days 1 and 7 (Food Effect Cohorts) at pre-dose and at 15, 30, 45 min and 1, 1.5, 2, 4, 6, 8, 12, 24, and 48 h post-dose.
SAD Cohorts 16 and 17: Day 1 at the same time-points as SAD Cohorts 8 - 15. MAD Cohorts 4 and 5: Day 1 at pre-dose and at 15, 30, 45 min and 1, 1.5, 2, 4, 6, 8, 12 h following start of the first dose (BID dosing) or pre-dose and at 15, 30, 45 min and 1, 1.5, 2, 4, 6 and 8 h following start of first dose and prior to second dose (TID dosing); Prior to the morning dose on Days 2, 3, 5, 7, 9, 11 and 13; Pre-dose, 15, 30, 45 min and 1, 1.5, 2, 4, 6, 8
Measured: SAD: Day 1 to Day 3 and Day 7 to 9 (food effect); MAD Day 1 to 16
Pharmacokinetics: SPR994 excreted in urine in each collection interval
SAD: Urine samples for PK will be collected at pre-dose and during the following intervals(total collection): 0-4, 4-8, 8-12, and 12-24 hours after dosing.
MAD: Urine samples for PK will be collected at pre-dose on Day 1 and during the followingintervals (total collection): 0-4, 4-8, and 8-12 hours after start of first dose (BID dosing) or pre-dose on Day 1 and during the following intervals (total collection): 0-4, 4-8 prior to next dose (Days 1-2); and 0-4, 4-8, 8-12, and 12-24 hours following start of the last dose (Days 14-15).
Measured: SAD: Days 1-2 and 7-8 (food effect cohorts). MAD: Day 1-2 and 14-15.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted10 Jan 2018
- Study start20 Oct 2017
- Primary completion2 Aug 2018
- Study completion2 Aug 2018
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Healthy VolunteersStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Randomized, double-blind, placebo-controlled, combined single and multiple ascending dose (SAD and MAD) trial
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 124 participants (actual)
Sponsor and investigators
- Lead sponsor
- Spero Therapeutics
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- CPR Pharma Services Pty Ltd, Australia
- Responsible party
- Sponsor
- Investigators
- Charlotte Lemech, FRACP, MD, Principal investigator, Scientia Clinical Research Limited
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03395249
- Sponsor's protocol ID
- SPR994-101
- Status last verified
- Mar 2018
- First submitted
- 19 Oct 2017
- Last updated
- 28 Aug 2018
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
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.
PubMed 31262768
Study at a glance
From the registry record, last updated by the sponsor on 28 Aug 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official 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
- ClinicalTrials.gov ID
- NCT03395249
- Acronym / sponsor ID
- SPR994-101
- Conditions
- Healthy Volunteers
- Keywords
- safety, tolerability, pharmacokinetics, SPR994
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 124 participants (actual)
- Lead sponsor
- Spero TherapeuticsIndustry (pharma, biotech, devices)
- Collaborators
- CPR Pharma Services Pty Ltd, Australia
- Study start
- 20 Oct 2017 (actual)
- Primary completion
- 2 Aug 2018 (actual)
- Study completion
- 2 Aug 2018 (actual)
- First posted
- 10 Jan 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
This study is a randomized, double-blind, placebo-controlled, combined single and multiple ascending dose (SAD and MAD) trial. Up to one hundred fifty two (152) subjects aged 18-55, who fulfill the inclusion/exclusion criteria, may be enrolled in this study. Up to a total of 17 SAD and 2 MAD cohorts of eight subjects each will be examined. Subjects in each cohort will be randomized 3:1 to receive SPR994 at doses ranging from 100 mg to 900 mg or placebo in various immediate and timed release formulations. One SAD control cohort, Cohort 12, may be enrolled in which eight subjects will receive a single dose of Orapenem® at 300 mg in a fed and fasted state. Dosing is complete in SAD Cohorts 1-3, 6 and 7. Subjects in Cohorts 1-3 received a single dose of SPR994 and subjects in food effect Cohorts 6 and 7 each received 2 doses. Subjects enrolled in SAD Cohorts 8 and beyond will receive a single dose of SPR994 or placebo in a fasted state and a second dose following a standardized meal to investigate food effect on the pharmacokinetics of SPR994 and TBPM. SAD Cohorts 8 through 10 may run in a staggered or concurrent manner before enrollment of further cohorts. Blinded pharmacokinetic data will be reviewed at the conclusion of Cohort 10 (300 mg fasted \& fed). Should the PK be optimized in one of the various time released formulations, the Sponsor may decide to proceed to enrollment of the 600 mg Cohorts using the optimal formulation; other timed release formulations may also be explored at 300 mg dose in a staggered or concurrent manner until an optimal formulation(s) is identified. When an optimal formulation(s) is identified, the 600 mg Cohorts may run in a staggered or concurrent manner. SAD Cohorts 16 (100 mg fasted) and 17 (900 mg fasted) may run prior to or in a staggered or concurrent manner with MAD Cohorts 4 (300 mg) and 5 (600 mg). During the MAD part of the study, subjects will receive 27 doses of SPR994 or placebo over a period of 14 days. Based on the observed PK of SPR994 in prior cohorts, the total number of doses may be increased to 40 doses of SPR994 or placebo administered TID over 14 days; only one dose will be administered on Day 14 to allow for PK sample collection In both SAD and MAD parts of the study, the Cohorts will be exposed to increasing doses of SPR994. Each part (SAD and MAD) of the study will consist of 3 periods: a screening period, a treatment period, and a follow-up period. The safety and tolerability of SPR994 will be assessed based on the types and frequency of adverse events (AEs) reported; concomitant medication usage; and changes from baseline in physical examination, weight, vital signs, ECG, and standard clinical laboratory tests. A Safety Management Group (SMG) will review the data of cohorts prior to escalating to the next dose level.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 3
- Model description
- Randomized, double-blind, placebo-controlled, combined single and multiple ascending dose (SAD and MAD) trial
| Arm | Type | Receives |
|---|---|---|
| SPR994, FI, F2, F3, F4 Oral Tablets | Experimental | Drug: SPR994SPR994 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 Oral Tablet | Placebo comparator | Drug: Placebo Oral TabletPlacebo 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 |
| Optional Orapenem Open-Label Control | Other | Drug: Orapenem®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. |
Who may qualify
- Ages
- 18 to 55 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (14 listed)
- 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:
- 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;
Key exclusion criteria (11 listed)
- 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);
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| SPR994Also: SPR994 Oral TabletSAD: 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. | Drug | SPR994, FI, F2, F3, F4 Oral Tablets |
| Placebo Oral TabletAlso: PlaceboMannitol 200SD SAD: Two subjects in each cohort will receive matching placebo. MAD: Two participants in each cohort will receive matching placebo. | Drug | Placebo Oral Tablet |
| Orapenem®Also: Orapenem® fine granulesTebipenem pivoxil granules | Drug | Optional Orapenem Open-Label Control |
Primary outcome
Safety measures: adverse events
Time frame: SAD: 1 to 7 days or 1 to 13 (food effect cohort); MAD 1 to 20 days
The incidence and severity of AEs
Safety measures: concomitant medications
Time frame: SAD: 1 to 7 days or 1 to 13 (food effect cohort); MAD: 1 to 20 days
The type and frequency of medications used
Safety measures: physical examination
Time frame: SAD: -1 to 7 days or -1 to 13 (food effect cohort); MAD: -1 to 20 days
Change from baseline to end of study visit
Safety measures: weight
Time frame: SAD: -1 to 7 days or -1 to 13 (food effect cohort); MAD: -1 to 20 days
Change from baseline to end of study visit
Safety measures: pulse rate
Time frame: SAD: -1 to 7 days or -1 to 13 (food effect cohort); MAD: -1 to 20 days
Change from baseline to end of study visit
Safety measures: ECG
Time frame: SAD: -1 to 7 days or -1 to 13 (food effect cohort); MAD: -1 to 20 days
Change from baseline to end of study visit
Safety measures: clinical laboratory testing
Time frame: SAD: -1 to 7 days or -1 to 13 (food effect cohort); MAD: -1 to 20 days
Change from baseline to end of study visit
Safety measures: respiratory rate
Time frame: SAD: -1 to 7 days or -1 to 13 (food effect cohort); MAD: -1 to 20 days
Change from baseline to end of study visit
Safety measures: blood pressure
Time frame: SAD: -1 to 7 days or -1 to 13 (food effect cohort); MAD: -1 to 20 days
Change from baseline to end of study visit
Safety measures: body temperature
Time frame: SAD: -1 to 7 days or -1 to 13 (food effect cohort); MAD: -1 to 20 days
Change from baseline to end of study visit
10 secondary outcomes
Pharmacokinetics: Time to maximum concentration (Tmax)
Time frame: SAD: Day 1 to Day 3 and Day 7 to 9 (Food Effect); MAD Day 1 to 16
Pharmacokinetics: Maximum concentration (Cmax)
Time frame: 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)
Time frame: 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)
Time frame: SAD: Day 1 to Day 3 and Day 7 to 9 (food effect); MAD Day 1 to 16
Pharmacokinetics: Terminal Elimination Rate Constant (kel)
Time frame: SAD: Day 1 to Day 3 and Day 7 to 9 (food effect); MAD Day 1 to 16
Pharmacokinetics: Terminal half-life (t1/2)
Time frame: SAD: Day 1 to Day 3 and Day 7 to 9 (food effect); MAD Day 1 to 16
Pharmacokinetics: Terminal clearance (CL/F)
Time frame: SAD: Day 1 to Day 3 and Day 7 to 9 (food effect); MAD Day 1 to 16
Pharmacokinetics: Volume of distribution
Time frame: 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 0 to 12 hours from the start of first dose (AUC0-12h)
Time frame: SAD: Day 1 to Day 3 and Day 7 to 9 (food effect); MAD Day 1 to 16
Pharmacokinetics: SPR994 excreted in urine in each collection interval
Time frame: SAD: Days 1-2 and 7-8 (food effect cohorts). MAD: Day 1-2 and 14-15.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 28 Aug 2018.
- Derived from this study: PubMed 31262768Eckburg 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Charlotte Lemech, FRACP, MD principal investigator
Scientia Clinical Research Limited
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing SPR994 and Orapenem® in people with Healthy Volunteers, run by Spero Therapeutics at 1 site in Australia.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 14 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 28 Aug 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Australia. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Safety measures: adverse events (time frame: SAD: 1 to 7 days or 1 to 13 (food effect cohort); MAD 1 to 20 days). The study lists 10 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03395249, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Aug 2018.