Pharmacodynamics, Safety, Tolerability and Pharmacokinetics of CDX-6114 in Patients With Phenylketonuria (PKU)

NCT04085666 | Completed Phase 1 DMC

• 1 other identifier: CDX6114-002
• Study Type: interventional
• Target: 18
• Locations: 2 countries
• Sites: 2

Brief Summary

This study is an international, multi-center, randomized, double-blind, placebo-controlled, two-treatment, two-period cross-over study to evaluate the pharmacodynamics, safety, tolerability and pharmacokinetics of a single oral dose of CDX-6114 in patients with phenylketonuria (PKU).

Conditions

Phenylketonuria

Outcome Measures

Primary Outcomes (6)

• Change in concentration of post parandial plasma level of Phe will be summarized over time for each treatment

  Blood samples will be collected at the following time points to determine the postprandial plasma levels of Phe following single does of CDX-6114

  Within 30 minutes, within 10 minutes and immediately prior to dosing, and then at 15 minutes, 30 minutes, 1hours, 1.5, 2,4 and 5hours after dosing on both Day 1 and Day 8

• Change in concentration of post parandial plasma level of CA will be summarized over time for each treatment

  Blood samples will be collected at the following time points to determine the postprandial plasma levels of CA following single does of CDX-6114

  Within 30 minutes, within 10 minutes and immediately prior to dosing, and then at 15 minutes, 30 minutes, 1hours, 1.5, 2,4 and 5hours after dosing on both Day 1 and Day 8

• Change in the peak Phe concentration in Plasma will be summarized by treatment

  Blood samples will be collected at the following time points to determine the Peak Phe plasma concentration follwoing a single, oral dose of CDX-6114

  Within 30 minutes, within 10 minutesand immediately prior to dosing, and then at 15 minutes, 30 minutes, 1, 1.5, 2, 4 and 5hours after dosing on both Day 1 and Day 8

• Change in the peak CA concentration in Plasma will be summarized by treatment

  Blood samples will be collected at the following time points to determine the Peak CA plasma concentration following a single, oral dose of CDX-6114

  Within 30 minutes, within 10 minutesand immediately prior to dosing, and then at 15 minutes, 30 minutes, 1, 1.5, 2, 4 and 5hours after dosing on both Day 1 and Day 8

• Phe Area under the plasma concentration versus time curve (AUC) , over a 5-hour period, following dosing and the standardized breakfast

  Blood samples will be collected at the following time points to determine the Phe AUC following a single, oral dose of CDX-6114

  Within 30 minutes, within 10 minutesand immediately prior to dosing, and then at 15 minutes, 30 minutes, 1, 1.5, 2, 4 and 5hours after dosing on both Day 1 and Day 8

• CA Area under the plasma concentration versus time curve (AUC) , over a 5-hour period, following dosing and the standardized breakfast

  Blood samples will be collected at the following time points to determine the CA AUC following a single, oral dose of CDX-6114

  Within 30 minutes, within 10 minutesand immediately prior to dosing, and then at 15 minutes, 30 minutes, 1, 1.5, 2, 4 and 5hours after dosing on both Day 1 and Day 8

Secondary Outcomes (12)

• Incidence of Treatment-Emergent Adverse Events (AEs) will be measured

  Within 30 minutes, within 10 minutes and immediately prior to dosing, and then at 15 minutes, 30 minutes, 1, 1.5, 2, 4 and 5hours after dosing on both Day 1 and Day 8

• The serum levels of CDX-6114 will be summarized descriptively over time

  Within 30 minutes, within 10 minutes and immediately prior to dosing, and then at 15 minutes, 30 minutes, 1, 1.5, 2, 4 and 5hours after dosing on both Day 1 and Day 8

• Absolute values and changes from baseline in blood pressure measurements will be summarized over time for each treatment

  Within 30 minutes prior to dosing, and then at 15 minutes, 30 minutes, 1, 1.5, 2, 4 and 5hours after dosing on both Day 1 and Day 8.

• Absolute values and changes from baseline in Heart rate measurements will be summarized over time for each treatment

  Within 30 minutes prior to dosing, and then at 15 minutes, 30 minutes, 1, 1.5, 2, 4 and 5hours after dosing on both Day 1 and Day 8.

• Absolute values and changes from baseline in Respiratory rate measurements will be summarized over time for each treatment

  Within 30 minutes prior to dosing, and then at 15 minutes, 30 minutes, 1, 1.5, 2, 4 and 5hours after dosing on both Day 1 and Day 8.

Study Arms (2)

1st Confinement Period in Unit

EXPERIMENTAL

Randomized to treatment with either CDX-6114 or matching Placebo

Drug: CDX 6114; Other: Matching Placebo

2nd Confinement Period in Unit

EXPERIMENTAL

Randomized to treatment with either CDX-6114 or matching Placebo

Drug: CDX 6114; Other: Matching Placebo

Interventions

CDX 6114 DRUG

CDX-6114 for oral administration is formulated in phosphate buffer, which also includes mannitol and poloxamer.The vehicle solution provided is identical to the CDX-6114 oral solution except for the active drug.

1st Confinement Period in Unit; 2nd Confinement Period in Unit

Matching Placebo OTHER

The placebo oral dosing solution will also be supplied as an approximately 240 mL oral solution and will be made up of the phosphate buffer diluent and the caramel flavoring.

1st Confinement Period in Unit; 2nd Confinement Period in Unit

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Male and female patients between the ages of 18 and 55 years (inclusive) with a diagnosis of classical PKU by either a historical blood Phe concentration of \> 1200 mol/L at any time or a genetic diagnosis of PKU.
• Patients capable of following dietary instructions to maintain protein intake stable throughout the study duration based on principal investigator and dietician assessment.
• Patients with a blood Phe concentration \< 1200mol/L at screening.
• Have a body mass index (BMI) between 18.0 and 30.0 kg/m2 inclusive and weigh at least 50 kg and no more than 100 kg inclusive.
• Patients must be in good general health, as determined by the PI or delegate, based on a medical evaluation including detailed medical history, full physical examination, including blood pressure and pulse rate measurement, 12-lead electrocardiogram (ECG) and clinical laboratory tests.
• Male patients (unless surgically sterilised) and their female spouse/partner(s) who are of childbearing potential:
• Must agree to stay abstinent (where abstinence is the preferred and usual life-style of the patient), starting at screening and continuing throughout the clinical study period, and for 90 days after last study drug administration.
• Must be using highly effective contraception starting at screening and continuing throughout the clinical study period, and for 90 days after last study drug administration. Highly effective contraception is defined as follows:
• i. Injectable or implantable hormones ii. Intrauterine device iii. Surgical sterilisation iv. Sterilisation implant device v. Combined oral contraceptives vi. Use of a condom plus oral or injectable or implantable or intrauterine contraception
• c. These requirements do not apply to participants in a same sex relationship.
• Male patients must agree not to donate sperm starting at screening and continuing throughout the clinical study period, and for 90 days after last study drug administration.
• Female patients of childbearing potential and their spouse/partner(s):
• Must agree not to become pregnant during the clinical study period and for 30 days after last study drug administration.
• Must have a negative serum pregnancy test at screening.
• If heterosexually active, must agree to consistently use a form of highly effective contraception, starting at screening and continuing throughout the clinical study period, and for 30 days after last study drug administration. Highly effective contraception is defined as follows:

You may not qualify if:

• Female patient who has been pregnant within the 6 months prior to screening or breastfeeding within the 3 months prior to screening.
• Evidence or history of clinically significant haematological, renal, endocrine, pulmonary, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies and childhood asthma) at time of screening.
• Current or chronic history of gastrointestinal illness or conditions interfering with normal gastrointestinal anatomy or motility. Examples include gastrointestinal bypass surgery, partial or total gastrectomy, small bowel resection, vagotomy, malabsorption, Crohn's disease, ulcerative colitis, irritable bowel syndrome (IBS) or celiac sprue.
• Evidence or history of gastrointestinal symptoms that could lead to the assumption of an underlying gastrointestinal impairment.
• Treatment with any anti-platelet and/or anticoagulant medication.
• Evidence or history of specific food intolerance. Examples include coeliac disease, severe lactose or dairy food intolerance or a severe intolerance to any food/ingredient included in the standard breakfast.
• Any positive result, on screening, for serum hepatitis B surface antigen (HBsAg), hepatitis C virus antibodies (HCV) or antibodies to human immunodeficiency virus type 1 (HIV-1) and/or type 2 (HIV-2).
• A positive drug/alcohol result.
• Patient has a history of exceeding \> 21 units of alcohol/week for male patients or \> 14 units of alcohol/week for female patients within the 3 months prior to screening. One unit of alcohol is equivalent to 5 ounces (150 mL) of wine or 12 ounces (360 mL) of beer or 1.5 ounces (45 mL) of spirits.
• Patient has a history of regular smoking (daily or most days in a week) or the use of nicotine products (3 or more nicotine-containing products) who would be unable to abstain from smoking during the confinement periods in the Phase 1 Unit.
• Patient has used any recreational drugs of abuse within the 3 months prior to screening.
• Patient has a pulse rate ≤ 50 or ≥ 100 bpm; mean systolic blood pressure (SBP) \> 140 mmHg; mean diastolic blood pressure (DBP) \> 90 mmHg at screening (excluding white-coat hypertension; therefore, a repeat test showing results within range will be acceptable).
• Patient has any clinically significant abnormalities at screening in rhythm, conduction or morphology of the resting ECG and any clinically significant abnormalities in the 12-lead ECG, as considered by the PI or delegate, which may interfere with the interpretation of QTc interval changes including abnormal ST-T wave morphology.
• Patient has prolonged QTcF (QT interval corrected for heart rate using Fridericia's formula) \> 450 ms for male patients or \> 470 ms for female patients, or a shortened QTcF \< 300 ms or a family history of prolonged QT syndrome, at screening.
• Patient has any clinically significant abnormalities in clinical chemistry, haematology, or urinalysis at screening as judged by the PI or delegate, including: Aspartate aminotransferase (AST), Alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma glutamyl transferase (GGT) or Total bilirubin (TBL) more than 2.0 times above the Upper Limit of Normal (ULN).

Sponsors & Collaborators

• Société des Produits Nestlé (SPN): lead

Study Sites (2)

Linear Clinical Research Ltd

Nedlands, Western Australia, 6009, Australia

Location

Profil Institut für Stoffwechselforschung GmbH

Neuss, D-41460, Germany

Location

MeSH Terms

Conditions

Phenylketonurias

Condition Hierarchy (Ancestors)

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; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Metabolic Diseases; Nutritional and Metabolic Diseases

Study Officials

• Damon Bell

  Linear Clinical Research

  PRINCIPAL INVESTIGATOR

• Tim Heise

  Profil Institut für Stoffwechselforschung GmbH

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: OTHER
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 3, 2019
• First Posted: September 11, 2019
• Study Start: June 1, 2019
• Primary Completion: June 30, 2020
• Study Completion: August 30, 2020
• Last Updated: September 14, 2020

Record last verified: 2020-09

Locations

AU (1); DE (1)