Clinical trial NCT03395249: Phase 1 Study of Safety, Tolerability and Pharmacokinetics of SPR994
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy Volunteers
Keywords: safety
tolerability
pharmacokinetics
SPR994
Lead sponsor: Spero Therapeutics
Sponsor class: INDUSTRY
Collaborators: name: CPR Pharma Services Pty Ltd, Australia
First posted: 2018-01-10
Enrollment: 124
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized, double-blind, placebo-controlled, combined single and multiple ascending dose (SAD and MAD) trial
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: 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.

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.

Primary outcomes:
measure: Safety measures: adverse events
timeFrame: SAD: 1 to 7 days or 1 to 13 (food effect cohort); MAD 1 to 20 days
measure: Safety measures: concomitant medications
timeFrame: SAD: 1 to 7 days or 1 to 13 (food effect cohort); MAD: 1 to 20 days
measure: Safety measures: physical examination
timeFrame: SAD: -1 to 7 days or -1 to 13 (food effect cohort); MAD: -1 to 20 days
measure: Safety measures: weight
timeFrame: SAD: -1 to 7 days or -1 to 13 (food effect cohort); MAD: -1 to 20 days
measure: Safety measures: pulse rate
timeFrame: SAD: -1 to 7 days or -1 to 13 (food effect cohort); MAD: -1 to 20 days
measure: Safety measures: ECG
timeFrame: SAD: -1 to 7 days or -1 to 13 (food effect cohort); MAD: -1 to 20 days
measure: Safety measures: clinical laboratory testing
timeFrame: SAD: -1 to 7 days or -1 to 13 (food effect cohort); MAD: -1 to 20 days
measure: Safety measures: respiratory rate
timeFrame: SAD: -1 to 7 days or -1 to 13 (food effect cohort); MAD: -1 to 20 days
measure: Safety measures: blood pressure
timeFrame: SAD: -1 to 7 days or -1 to 13 (food effect cohort); MAD: -1 to 20 days
measure: Safety measures: body temperature
timeFrame: SAD: -1 to 7 days or -1 to 13 (food effect cohort); MAD: -1 to 20 days
Secondary outcomes:
measure: Pharmacokinetics: Time to maximum concentration (Tmax)
timeFrame: SAD: Day 1 to Day 3 and Day 7 to 9 (Food Effect); MAD Day 1 to 16
measure: Pharmacokinetics: Maximum concentration (Cmax)
timeFrame: SAD: Day 1 to Day 3 and Day 7 to 9 (Food Effect); MAD Day 1 to 16
measure: Pharmacokinetics: Area under the concentration-time curve from time 0 to last measurable time-point (AUC0-t)
timeFrame: SAD: Day 1 to Day 3 and Day 7 to 9 (food effect); MAD Day 1 to 16
measure: Pharmacokinetics: Area under the concentration-time curve from time 0 to infinity (AUC0-inf)
timeFrame: SAD: Day 1 to Day 3 and Day 7 to 9 (food effect); MAD Day 1 to 16
measure: Pharmacokinetics: Terminal Elimination Rate Constant (kel)
timeFrame: SAD: Day 1 to Day 3 and Day 7 to 9 (food effect); MAD Day 1 to 16
measure: Pharmacokinetics: Terminal half-life (t1/2)
timeFrame: SAD: Day 1 to Day 3 and Day 7 to 9 (food effect); MAD Day 1 to 16
measure: Pharmacokinetics: Terminal clearance (CL/F)
timeFrame: SAD: Day 1 to Day 3 and Day 7 to 9 (food effect); MAD Day 1 to 16
measure: Pharmacokinetics: Volume of distribution
timeFrame: SAD: Day 1 to Day 3 and Day 7 to 9 (food effect); MAD Day 1 to 16
measure: Pharmacokinetics: Area under the concentration-time curve from 0 to 12 hours from the start of first dose (AUC0-12h)
timeFrame: SAD: Day 1 to Day 3 and Day 7 to 9 (food effect); MAD Day 1 to 16
measure: Pharmacokinetics: SPR994 excreted in urine in each collection interval
timeFrame: SAD: Days 1-2 and 7-8 (food effect cohorts). MAD: Day 1-2 and 14-15.
Other outcomes:
Locations:
city: Randwick
country: Australia
facility: Scientia Clinical Research Ltd
state: New South Wales
Study officials:
affiliation: Scientia Clinical Research Limited
name: Charlotte Lemech, FRACP, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.