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Safety and Tolerability of SYNB1618 in Healthy Adult Volunteers and Adult Subjects With Phenylketonuria (PKU)

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ClinicalTrials.gov Identifier: NCT03516487
Recruitment Status : Recruiting
First Posted : May 4, 2018
Last Update Posted : June 14, 2018
Sponsor:
Information provided by (Responsible Party):
Synlogic

Brief Summary:
This study will evaluate SYNB1618 (investigational product) in healthy volunteers (HV) and subjects diagnosed with phenylketonuria (PKU) for the possible treatment of PKU. Phenylketonuria (PKU) is a rare inherited metabolic disorder that occurs in people who are missing an enzyme that the body needs to use phenylalanine. Eligible subjects will receive investigational product (IP) in the clinic, and will undergo safety monitoring, evaluations and subsequent follow-up after IP administration.

Condition or disease Intervention/treatment Phase
Phenylketonuria Healthy Drug: SYNB1618 Drug: Placebo Phase 1 Phase 2

Detailed Description:

This Phase 1/2a, first-in-human, oral single and multiple dose-escalation, randomized, double-blinded, placebo-controlled study of SYNB1618 in healthy adult volunteers and adult subjects with phenylketonuria will evaluate safety, tolerability, kinetics, and pharmacodynamics within the following 2 study parts:

Part 1 comprises a single-ascending dose (SAD) study conducted (3 treated:1 placebo) over 4 days in HV male and female subjects evaluated in up to 6 dose cohorts to identify maximum tolerated dose (MTD) within the single dose-dose range studied. Up to 24 healthy subjects may be enrolled in this part of the study. Following attainment of the MTD in HV, a SAD cohort of up to 4 subjects (male and female, >18 years old) previously diagnosed with PKU will be enrolled (3 treated:1 placebo).

Part 2 comprises a multiple-ascending dose (MAD) study conducted in an inpatient setting (6 treated:2 placebo) over 10 days in HV male and female subjects evaluated in up to 4 cohorts at doses that will not exceed the MTD from the SAD part of the study to identify the MTD of SYNB1618 within the multiple-dose range studied. Up to 32 healthy subjects may be enrolled in this part of the study. Once the highest MAD cohort and the SAD PKU cohort have been completed, a multiple-dose cohort of male and female subjects (>18 years old) previously diagnosed with PKU will be evaluated. Up to 20 subjects with PKU may be enrolled in the MAD PKU cohort (12 treated: 8 placebo).


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 80 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Dose-escalating, Randomized, Double-blinded, Placebo-controlled
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Double-blind
Primary Purpose: Treatment
Official Title: A Phase 1/2a, First-in-human, Oral Single and Multiple Dose-Escalation, Randomized, Double-blinded, Placebo-controlled Study of SYNB1618 in Healthy Adult Volunteers and Adult Subjects With Phenylketonuria to Evaluate Safety, Tolerability, Kinetics, and Pharmacodynamics
Actual Study Start Date : April 2, 2018
Estimated Primary Completion Date : August 2019
Estimated Study Completion Date : September 2019


Arm Intervention/treatment
Experimental: SYNB1618
A single or multiple oral dose of SYNB1618 in a chilled buffered solution
Drug: SYNB1618
A single (Part 1) or multiple (Part 2) ascending oral dose of SYNB1618 in a buffered solution. In Part 1, subjects receive one dose of SYNB1618 on Day 1. In Part 2, subjects receive SYNB1618 TID for 7 days.

Placebo Comparator: Placebo
A single or multiple oral dose of placebo (100mL of a chilled buffer solution)
Drug: Placebo
A single (Part 1) or multiple (Part 2) oral dose of a buffered 100mL solution. In Part 1, subjects receive one dose of buffered solution on Day 1. In Part 2, subjects receive a buffered solution TID for 7 days.




Primary Outcome Measures :
  1. Incidence of treatment-emergent Adverse Events [ Time Frame: Up to 90 days following enrollment. ]
    Will be measured by assessing nature and frequency of Adverse Events.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 64 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  1. Age > 18 to ≤ 64 years.
  2. Able and willing to voluntarily complete the informed consent process (subject or subject's representative).
  3. Available for and agree to all study procedures, including feces, urine, and blood collection and adherence to diet control, inpatient monitoring, follow-up visits, and IP ingestion compliance.
  4. Male subjects who are sexually abstinent or surgically sterilized (vasectomy), or those who are sexually active with a female partner(s) and agree to use an acceptable method of contraception (such as condom with spermicide) combined with an acceptable method of contraception for their non-pregnant female partner(s) (as defined in Inclusion Criterion #5) after informed consent, throughout the study, and for a minimum of 90 days after the last dose of IP, and who do not intend to donate sperm in the period from screening until 3 months following administration of the investigational medical product.
  5. Female subjects that meet one of the following:

    1. Woman of childbearing potential (WOCBP) must have a negative serum pregnancy test (HCG) at screening and at baseline prior to the start of IP and must agree to use acceptable method(s) of contraception, combined with an acceptable method of contraception for their male partner(s) (as defined in Inclusion Criterion #4) after informed consent, throughout the study and for a minimum of 90 days after the last dose of IP. Acceptable methods of contraception include hormonal contraception, hormonal or non-hormonal intrauterine device, bilateral tubal occlusion, complete abstinence, vasectomized partner with documented azoospermia 90 days after procedure, diaphragm with spermicide, cervical cap with spermicide, vaginal sponge with spermicide, or male or female condom with or without spermicide.
    2. Premenopausal woman with one of the following:

    i. Documented hysterectomy ii. Documented bilateral salpingectomy iii. Documented bilateral oophorectomy iv. Documented tubal ligation/occlusion v. Sexual abstinence is preferred or usual lifestyle of the subject c. Postmenopausal woman (12 months or more amenorrhea verified by follicle stimulating hormone [FSH] assessment and over 45 years of age in the absence of other biological or physiological causes).

  6. Screening laboratory evaluations (e.g., chemistry panel, CBC with differential, prothrombin time [PT]/activated partial thromboplastin time [aPTT], urinalysis, C reactive protein [CRP], creatinine clearance) and ECG must be within normal limits or judged to be not clinically significant by the Investigator.
  7. Stable diet including protein intake for at least 60 days prior to study enrollment.
  8. Able to produce at least 2 bowel movements per week on average without the assistance of laxatives.

    In addition to the above criteria for HV, inclusion criteria for PKU subjects are as noted below.

  9. Diagnosis of classic PKU by either medical history of blood Phe concentration of >1200 µmol/L at any time OR genetic diagnosis.
  10. Blood Phe concentration of ≥ 600 µmol/L at Screening.
  11. Stable diet including stable medical formula regimen (if used) for 3 months prior to screening assessments.

Exclusion Criteria:

  1. Acute or chronic medical, surgical, psychiatric, or social condition or laboratory abnormality that may increase subject risk associated with study participation, compromise adherence to study procedures and requirements, or may confound interpretation of study safety or PD results and, in the judgment of the investigator, would make the subject inappropriate for enrollment.
  2. Body mass index < 18.5 or ≥ 30 kg/m2 (> 40 kg/m2 for PKU subjects).
  3. History of or current immunodeficiency disorder including autoimmune disorders and human immunodeficiency virus (HIV) antibody positivity.
  4. Hepatitis B surface antigen positivity (subjects with hepatitis B surface antibody positivity and hepatitis B core antibody positivity are not excluded, provided that the hepatitis B surface antigen is negative).
  5. Hepatitis C antibody positivity, unless a hepatitis C virus ribonucleic acid test is performed and the result is negative.
  6. History of febrile illness, confirmed bacteremia, or other active infection within 30 days prior to the anticipated first dose of IP.
  7. History of active or chronic passage of 3 or more loose stools per day.
  8. Active or past history of laxative use within 60 days prior to the Screening Visit.
  9. Active inflammatory or irritable bowel disorder of any grade.
  10. Active or past history of gastrointestinal (GI) bleeding within 60 days prior to the Screening Visit as confirmed via hospitalization-related event(s) or medical history of hematemesis or hematochezia.
  11. Intolerance of or allergic reaction to E. coli Nissle or any of the ingredients in SYNB1618 or placebo formulations; allergies to common foods (e.g., eggs, milk, soy, nuts).
  12. Any condition, prescription medication, or over-the-counter product that may possibly affect absorption of medications or nutrients (e.g., celiac disease, gastrectomy, bypass surgery, ileostomy).
  13. Currently taking or plans to take any type of systemic (e.g., oral or intravenous) antibiotic within 28 days prior to the Screening Visit through the final outpatient follow-up. Exception: topical antibiotics are allowed.
  14. Surgery or inpatient hospital stay within the past 6 months.
  15. Planned surgery, hospitalizations, dental, or interventional studies between screening and last anticipated visit that might require antibiotics.
  16. Taking or planning to take probiotic supplements (enriched foods excluded) within 28 days prior to the Screening Visit and for the duration of participation and follow-up.
  17. Dependence on drugs of abuse or positive urine drug screen for drugs of abuse (including smoking or nicotine use).
  18. Regular alcohol consumption in excess of 14 standard drinks/week for men and in excess of 7 standard drinks/week for women and/or any evidence of binge or heavy drinking (according to National Institute on Alcohol Abuse and Alcoholism guidelines). One drink is equivalent to 12 g of alcohol: 12 ounces (360 mL) of beer, 5 ounces (150 mL) of wine or 1.5 ounces (45 mL) of 80 proof distilled spirits.
  19. Administration or ingestion of an investigational drug within 60 days or 5 half-lives, whichever is longer, prior to the Screening Visit or current enrollment in an investigational study. (PKU subjects who participated in the PKU SAD cohort may be eligible for screening for the PKU MAD cohort > 30 days after the last dose of IP.)
  20. Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, GI, cardiovascular (including stable coronary artery disease/angina or prior cardiac stent), hepatic, neurologic, or allergic disease including drug allergies.
  21. Screening laboratory parameters within the acceptable range.

    In addition to the above criteria for HV, exclusion criteria for PKU subjects are as noted below.

  22. Currently taking (within the past 6 months) sapropterin (KUVAN®) or pegylated recombinant phenylalanine ammonia lyase (PEG-PAL)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03516487


Contacts
Contact: Kendall Davis 919-788-6519 JamesDavisKendall@prahs.com

Locations
United States, Utah
PRA Health Sciences Recruiting
Salt Lake City, Utah, United States, 84124
Contact: Christian Ventrello    801-904-4662    VentrelloChristian@prahs.com   
Principal Investigator: Shawn Searle, MD         
Sponsors and Collaborators
Synlogic

Responsible Party: Synlogic
ClinicalTrials.gov Identifier: NCT03516487     History of Changes
Other Study ID Numbers: SYNB1618-CP-001
First Posted: May 4, 2018    Key Record Dates
Last Update Posted: June 14, 2018
Last Verified: June 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Synlogic:
PKU

Additional relevant MeSH terms:
Phenylketonurias
Brain Diseases, Metabolic, Inborn
Brain Diseases, Metabolic
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Amino Acid Metabolism, Inborn Errors
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Metabolic Diseases
Pharmaceutical Solutions