Clinical trial NCT03701555: A Study of PVP001, PVP002, and PVP003 in Healthy Adults and PVP001 and PVP002 in Adults With Celiac Disease
Official title: A Phase 1, Four-Part Study to Assess the Safety, Tolerability, Pharmacokinetics, and Gluten Degradation Activity of PvP001, PvP002, and PvP003 in Healthy Adult Volunteers and to Assess the Safety, Tolerability, and Pharmacokinetics of PvP001 and PvP002 in Adults With Celiac Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Digestive System Disease
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2018-10-10
Enrollment: 139
Sex: ALL
Minimum age (years): 18
Maximum age (years): 64
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: BASIC_SCIENCE

Brief summary: It is hoped that different forms of the same medicine, called PVP001, PVP002, and PVP003, will help people with celiac disease. Both healthy adults and adults with celiac disease will take part in this study.

There are many main aims of the study.

* To check if participants have side effects from different forms of the study medicine. These forms are called PVP001 (liquid in a cup), PVP002 capsule, and PVP003 tablet.
* To check how well PVP003 breaks down gluten.
* To check how much PVP003 participants can take without getting side effects from it.

The study is in 4 parts. At the start of each part of the study, the study doctor will check to determine who can take part at the first study visit. Different groups of participants will be in different parts of the study.

In all parts of the study, some participants will take 1 of the 3 forms of study medicine. Others will take a placebo. In this study, a placebo will look like the form of study medicine but will not have any medicine in it. This means that a placebo can either look like PVP001 liquid in a cup, the PVP002 tablet, or the PVP003 tablet.

In Part 1, different small groups of participants will take lower to higher doses of PVP001 or PVP002 or a placebo. This is to work out the best dose of study medicine to take in other parts of the study. After treatment, participants will regularly visit the clinic to check that they have no problems with their treatment, including any side effects from their treatment.

In Part 2, different small groups will take different doses of PVP001 or PVP002 or a placebo, either with or without a meal that has different amounts of gluten in it. This is to check if PVP001 or PVP002 has broken down gluten in the body. Participants will visit the clinic after treatment to check how much gluten has been broken down in the body.

In Part 3, different small groups will take different doses of PVP003 or a placebo, either with or without a meal that has gluten in it. This is to check if PVP003 has broken down gluten in the body. Participants will visit the clinic after treatment to check if more gluten has broken down in the body.

In Part 4, different small groups will take PVP003 or placebo 3 times a day for 5 days. After treatment, participants will visit the clinic to check that they have no problems with their treatment, including any side effects from their treatment.

Detailed description: This study has four parts. Each part of the study begins with a Screening Period of up to 4 weeks to allow for completion of screening procedures and subject scheduling. Each participant will be screened by means of medical history, medication review, Gastrointestinal Symptoms Questionnaire (GSQ), physical examination, vital signs, weight, height, laboratory tests, and ECG. The GSQ is being used as a separate safety monitoring tool in this study to ensure that all gastrointestinal complaints are reported by the participant.

Following completion of all screening procedures, eligible participants will be enrolled in the study.

Part 1 of the study in healthy participants will be completed prior to enrollment of any subject in Part 2 of the study. A participant enrolled in Part 1 of the study will participate in one of five dose Cohorts. Enrollment of healthy participants and participants with CeD in each of the five dose Cohorts will occur sequentially, but each of these dose Cohorts will be open to enrollment only after demonstration of the safety and tolerability of the same dose level in healthy participants. A healthy participant enrolled in Part 2 of the study will participate in one of three groups; within Groups 1, 2 and 3 enrollment may occur in parallel. A healthy participant enrolled in Part 3 of the study will participate in one of five groups; within Groups 1 to 5 enrollment will occur sequentially. A healthy participant enrolled in Part 4 of the study will participate in two cohorts; enrollment in Part 4 may occur in parallel with enrollment in Part 3. Each participant will be randomized to one of two possible treatment order. Participants who participate in Part 1 or Part 2 of the study, and who are not ADA positive, may participate in Part 3 or Part 4 of the study. No other participants may participate in more than one Part/Group of the study.

Eligibility criteria: Inclusion Criteria:

Part 1, Part 2, Part 3 and Part 4

1. Male or female age 18- 64 years, inclusive
2. No relevant gastrointestinal symptoms
3. Able to abstain from alcohol for 72 hours prior to the Screening Visit; for 72 hours prior to and after the Cohort Treatment Day (Part 1, Part 2, and Part 3); for 72 hours prior to the Safety Visit (Part 2 and Part 3); and for 72 hours prior to Day 1 of the first Cohort Treatment Period through the Safety Visit (Part 4).
4. A female participant must have a negative pregnancy test at Screening and on Cohort Treatment Day -1 (Part 1, Part 2, and Part 3) or a negative pregnancy test at Screening and on Day -1 of each Cohort Treatment Period (Part 4), and must agree to continue acceptable birth control measures (example, abstinence, a stable hormonal contraceptive, double-barrier method, or vasectomy in partner) from the Screening Visit through the 28 ± 2 days. Follow Up ADA Blood Sampling Visit
5. A male participant must agree to use acceptable birth control measures (e.g., abstinence, latex condom, or vasectomy), or must have a female partner who will continue birth control measures (e.g., abstinence, a stable hormonal contraceptive, or double-barrier method) from the Screening Visit through the 28 ± 2 days Follow Up Anti-Drug Antibody Blood Sampling Visit
6. Able to read and understand English
7. Able to provide written informed consent

   Additional Inclusion Criteria for Part 1, Part 2, Part 3, and Part 4 Healthy Adult Volunteers
8. No use of over-the-counter or prescription medication, except for birth control medications for the duration of the study
9. No history of gastrointestinal diseases or disorders
10. No history of intolerance, sensitivity, or reactions to gluten or any other food or food ingredient
11. Able to maintain a gluten-free diet for 24 hours prior to the Cohort Treatment Day (Part 1, Part 2, and Part 3), or usually ingests meals three times a day (that is, breakfast, lunch, and dinner) and is able to continue doing so during each Cohort Treatment Period (Part 4)

    Additional Inclusion Criteria for Part 1 Participants with Celiac Disease
12. Documented history of Celiac Disease in medical records
13. Maintaining a gluten-free diet for ≥6 months
14. No use of over-the-counter or prescription medication, except for birth control medications and those allowed by the study doctor, for the duration of the study.
15. No history of gastrointestinal diseases or disorders, other than Celiac Disease
16. No history of intolerance, hypersensitivity, or reaction to any food or food ingredient
17. Able to continue a gluten-free diet for the duration of the study

Exclusion Criteria:

Part 1, Part 2, Part 3, and Part 4

1. Current symptoms or signs of illness
2. Chronic viral infection or immunodeficiency condition
3. Any female who is pregnant, planning to become pregnant during the study, or breast-feeding; any male who is planning to father a child during the study
4. Receipt (or planned receipt) of another investigational medication within 4 weeks prior to the Screening Visit through the duration of the study
5. Alcohol consumption greater than (\>) 5 drinks/week, alcohol consumption within 72 hours prior to any study visit (Part 1, Part 2, and Part 3), alcohol consumption within 72 hours prior to Day 1 of the first Cohort Treatment Period through the Safety Visit (Part 4), or a positive alcohol breathalyzer test at any study visit
6. History of illicit or recreational drug use within the three years prior to the Screening Visit, or a positive urine drug screen at any study visit
7. Use of tobacco or nicotine products, including smoking, smokeless tobacco, e-cigarettes, or nicotine replacement products within 12 months prior to the Screening Visit through the duration of the study

Primary outcomes:
measure: Part 1: Number of Participants Reporting One or More Treatment Emergent Adverse Events (TEAEs) for PvP001 and PvP002
timeFrame: Cohort Treatment Day up to 5 days after 24-hour safety assessment on Day 2 (up to Day 7)
measure: Part 4: Number of Participants Reporting One or More TEAEs for PvP003 After Multiple Doses
timeFrame: Day 1 of Cohort Treatment Period 1 up to 5 days after the Day 5 of Cohort Treatment Period 2 (up to Day 28)
measure: Part 1: Number of Participants Reporting One or More Treatment Emergent Serious Adverse Events (TESAEs) for PvP001 and PvP002
timeFrame: Cohort Treatment Day up to 5 days after 24-hour safety assessment on Day 2 (up to Day 7)
measure: Part 4: Number of Participants Reporting One or More TESAEs for PvP003 600 mg After Multiple Doses
timeFrame: Day 1 of Cohort Treatment Period 1 up to 5 days after the Day 5 of Cohort Treatment Period 2 (up to Day 28)
measure: Part 2, Group 1, Cohort 2B: Median Percentage of Gluten Degradation by PvP001 in a Standardized 3 Gram (gm) Gluten-containing Study Meal After Administration of PvP001
timeFrame: Cohort Treatment Day
measure: Part 2, Group 2, Cohort 2E: Median Percentage of Gluten Degradation by PvP002 in a Standardized 3 gm Gluten-containing Study Meal After Administration of PvP002
timeFrame: Cohort Treatment Day
measure: Part 2, Group 1, Cohort 2C: Median Percentage of Gluten Degradation by PvP001 in a Standardized 3 gm Gluten-containing Study Meal Following 7 Days of Standard Dose PPI Treatment
timeFrame: Cohort Treatment Day
measure: Part 2, Group 3, Cohort 2G and 2H: Median Percentage of Gluten Degradation by PvP001 300 mg and 600 mg in a Standardized 1 gm Gluten-containing Study Meal at 20 Minutes After Administration of PvP001
timeFrame: Cohort Treatment Day: at 20 minutes post-dose
measure: Part 2, Group 3, Cohort 2G and 2H: Median Percentage of Gluten Degradation by PvP001 300 mg and 600 mg in a Standardized 1 gm Gluten-containing Study Meal at 35 Minutes After Administration of PvP001
timeFrame: Cohort Treatment Day: at 35 minutes post-dose
measure: Part 2, Group 3, Cohort 2G and 2H: Median Percentage of Gluten Degradation by PvP001 300 mg and 600 mg in a Standardized 1 gm Gluten-containing Study Meal at 65 Minutes After Administration of PvP001
timeFrame: Cohort Treatment Day: at 65 minutes post-dose
measure: Part 2, Group 3, Cohort 2J: Median Percentage of Gluten Degradation by PvP001 900 mg in a Standardized 6 gm Gluten-containing Study Meal at 20 Minutes After Administration of PvP001
timeFrame: Cohort Treatment Day: at 20 minutes post-dose
measure: Part 2, Group 3, Cohort 2J: Median Percentage of Gluten Degradation by PvP001 900 mg in a Standardized 6 gm Gluten-containing Study Meal at 35 Minutes After Administration of PvP001
timeFrame: Cohort Treatment Day: at 35 minutes post-dose
measure: Part 2, Group 3, Cohort 2J: Median Percentage of Gluten Degradation by PvP001 900 mg in a Standardized 6 gm Gluten-containing Study Meal at 65 Minutes After Administration of PvP001
timeFrame: Cohort Treatment Day: at 65 minutes post-dose
measure: Part 3, Groups 1 to 5, Cohorts 3B, 3D, 3F, 3H and 3J: Median Percentage of Gluten Degradation by PvP003 150 mg and 600 mg in a Standardized 1 gm Gluten-containing Study Meal at 35 Minutes After Administration of PvP003
timeFrame: Cohort Treatment Day: at 35 minutes
measure: Part 3, Groups 1 to 5, Cohorts 3B, 3D, 3F, 3H and 3J: Median Percentage of Gluten Degradation by PvP003 150 mg and 600 mg in a Standardized 1 gm Gluten-containing Study Meal at 65 Minutes After Administration of PvP003
timeFrame: Cohort Treatment Day: at 65 minutes
Secondary outcomes:
measure: Part 1 and Part 2, Cmax: Maximum Observed Plasma Concentration for PvP001 and PvP002
timeFrame: Cohort Treatment Day pre-dose and at multiple time points (up to 480 minutes) post-dose
measure: Part 1 and Part 2, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for PvP001 and PvP002
timeFrame: Cohort Treatment Day pre-dose and at multiple time points (up to 480 minutes) post-dose
measure: Part 1 and Part 2, T(1/2): Terminal Disposition Phase Half-life of PvP001 and PvP002
timeFrame: Cohort Treatment Day pre-dose and at multiple time points (up to 480 minutes) post-dose
measure: Part 1 and Part 2, AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for PvP001 and PvP002
timeFrame: Cohort Treatment Day pre-dose and at multiple time points (up to 480 minutes) post-dose
measure: Part 1 and Part 2, AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for PvP001 and PvP002
timeFrame: Cohort Treatment Day pre-dose and at multiple time points (up to 480 minutes) post-dose
measure: Part 1 and Part 2: Number of Participants With Anti-drug Antibodies (ADA) for PvP001 and PvP002
timeFrame: At Day 14 and Day 28
measure: Part 1: Maximum Tolerated Dose (MTD) of PvP001
timeFrame: Cohort Treatment Day up to Day 7
measure: Part 2: Number of Participants Reporting One or More TEAEs and TESAEs for PvP001 and PvP002
timeFrame: Cohort Treatment Day up to 5 days after the final Cohort Treatment Day (up to Day 22)
measure: Part 3: Number of Participants Reporting One or More TEAEs and TESAEs With PvP003 After a Single Dose
timeFrame: Cohort Treatment Day up to 5 days after final Cohort Treatment Day (up to Day 10)
measure: Part 3, Cmax: Maximum Observed Plasma Concentration for PvP003 150 mg and 600 mg Single Dose
timeFrame: Cohort Treatment Day pre-dose and at multiple time points (up to 480 minutes) post-dose
measure: Part 3, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for PvP003 150 mg and 600 mg Single Dose
timeFrame: Cohort Treatment Day pre-dose and at multiple time points (up to 480 minutes) post dose
measure: Part 3, T(1/2): Terminal Disposition Phase Half-life of PvP003 150 mg and 600 mg Single Dose
timeFrame: Cohort Treatment Day pre-dose and at multiple time points (up to 480 minutes) post dose
measure: Part 3, AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for PvP003 150 mg and 600 mg Single Dose
timeFrame: Cohort Treatment Day pre-dose and at multiple time points (up to 480 minutes) post dose
measure: Part 3, AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for PvP003 150 mg and 600 mg Single Dose
timeFrame: Cohort Treatment Day pre-dose and at multiple time points (up to 480 minutes) post dose
measure: Part 3: Number of Participants With ADA for PvP003 150 mg and 600 mg Single Dose
timeFrame: At Day 14 and Day 28
measure: Part 4, Cmax: Maximum Observed Plasma Concentration for PvP003 600 mg Multiple Dose
timeFrame: Cohort Treatment Days 1 and 5 pre-dose and at multiple time points (up to 240 minutes) post dose
measure: Part 4, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for PvP003 600 mg Multiple Dose
timeFrame: Cohort Treatment Days 1 and 5 pre-dose and at multiple time points (up to 240 minutes) post dose
measure: Part 4, T(1/2): Terminal Disposition Phase Half-life of PvP003 600 mg Multiple Dose
timeFrame: Cohort Treatment Days 1 and 5 pre-dose and at multiple time points (up to 240 minutes) post dose
measure: Part 4, AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for PvP003 600 mg Multiple Dose
timeFrame: Cohort Treatment Days 1 and 5 pre-dose and at multiple time points (up to 240 minutes) post dose
measure: Part 4, AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for PvP003 600 mg Multiple Dose
timeFrame: Cohort Treatment Days 1 and 5 pre-dose and at multiple time points (up to 240 minutes) post dose
measure: Part 4: Number of Participants With ADA for PvP003 600 mg Multiple Dose
timeFrame: At Day 14 and Day 28
Other outcomes:
Locations:
city: Anaheim
country: United States
facility: Anaheim Clinical Trials
state: California
Study officials:
affiliation: Takeda
name: Study Director
role: STUDY_DIRECTOR
References:
citation: Pultz IS, Hill M, Vitanza JM, Wolf C, Saaby L, Liu T, Winkle P, Leffler DA. Gluten Degradation, Pharmacokinetics, Safety, and Tolerability of TAK-062, an Engineered Enzyme to Treat Celiac Disease. Gastroenterology. 2021 Jul;161(1):81-93.e3. doi: 10.1053/j.gastro.2021.03.019. Epub 2021 Mar 17.