Phase 1 Study of ALXN1840 on the Metabolism of a CYP2C9 Substrate in Healthy Participants.

Study Overview
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Brief Summary
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This was a Phase 1, randomized, 2-period, 2-sequence, cross-over study designed to determine the effect of ALXN1840 on the metabolism of celecoxib, a sensitive cytochrome P450 2C9 (CYP2C9) substrate, in healthy male and female participants. The safety and tolerability of ALXN1840 were determined along with ALXN1840 pharmacokinetics (PK) in plasma as measured via total molybdenum with the coadministration of celecoxib.

Detailed Description
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The study was conducted as a randomized, 2-period, 2-sequence, cross-over study to determine the effect of a single dose of ALXN1840 (perpetrator) on the single-dose celecoxib (victim) kinetics in healthy male and female participants. The study had a Screening period (Day -28 to Day -2), two 11-day study periods (Day 1 to Day 11) with a minimum of 14 days between doses of celecoxib, and an End of Study Visit (Day 15 ± 2 days) after Period 2 dosing. Participants only reported to the clinical research unit (CRU) on the day prior to the first dose because they were kept in the CRU during the wash-out period due to coronavirus disease 2019. All participants received a single dose of celecoxib alone (Treatment A) and celecoxib coadministered with ALXN1840 (Treatment B) during the study, 1 in each treatment period. Based on randomization, participants were administered either Treatments A-B or Treatments B-A in each study period. The PK profile of ALXN1840 and celecoxib was determined by blood sampling following single-dose administration. In addition to PK sampling, safety and tolerability were assessed by monitoring adverse events, vital signs, 12-lead electrocardiograms, physical examinations, and laboratory parameters.

Official Title
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A Phase 1, Randomized, 2-Period, 2-Sequence, Cross-over Study to Determine the Effect of ALXN1840 on the Metabolism of a CYP2C9 Substrate in Healthy Participants.

Conditions
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Wilson Disease

Intervention / Treatment
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* Drug: ALXN1840
* Drug: Celecoxib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adequate venous access in the left or right arm to allow the collection of blood samples. Bodyweight ≥ 45 to ≤ 100 kilograms (kg) and body mass index within the range of 18 to < 30 kg/meter squared. Willing and able to follow protocol-specified contraception requirements. Capable of giving signed informed consent. Exclusion Criteria: History or presence of/significant medical history. Clinically significant multiple or severe allergies. Lymphoma, leukemia, or any malignancy within 5 years. Breast cancer within the past 10 years. Serum creatinine > upper limit of normal (ULN) of the reference range. Alanine aminotransferase, aspartate aminotransferase, or total bilirubin > ULN. Current or chronic history of liver disease or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones). QTc > 450 milliseconds (msec) for male participants or > 470 msec for female participants.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Participants were randomized to 1 of 2 treatment sequences: A-B or B-A.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Sequence A-B<br>Participants received 1 treatment during each study period in the following sequence: Treatment A: Celecoxib. Treatment B: Celecoxib plus ALXN1840. | Drug: ALXN1840<br>* ALXN1840 was administered orally as a single dose as 4 x 15 milligram (mg) enteric-coated tablets with 240 milliliters (mL) of water (fasting), for a total dose of 60 mg.<br>* Other names: Tiomolibdate choline;Drug: Celecoxib<br>* Celecoxib was administered orally as a single dose as one 200-mg tablet with 240 mL of water (fasting).<br>|
| Experimental: Treatment Sequence B-A<br>Participants received 1 treatment during each study period in the following sequence: Treatment B: Celecoxib plus ALXN1840. Treatment A: Celecoxib. | Drug: ALXN1840<br>* ALXN1840 was administered orally as a single dose as 4 x 15 milligram (mg) enteric-coated tablets with 240 milliliters (mL) of water (fasting), for a total dose of 60 mg.<br>* Other names: Tiomolibdate choline;Drug: Celecoxib<br>* Celecoxib was administered orally as a single dose as one 200-mg tablet with 240 mL of water (fasting).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Plasma Concentration (Cmax) Of Celecoxib With And Without The Coadministration Of ALXN1840 | Blood samples were collected for pharmacokinetics (PK) analysis of celecoxib. Cmax is reported as nanograms (ng)/milliliter (mL). | Baseline, up to 336 hours post-dose | 
| Area Under The Plasma Concentration Versus Time Curve From Time 0 To The Last Quantifiable Concentration (AUCt) Of Celecoxib With And Without The Coadministration Of ALXN1840 | Blood samples were collected for pharmacokinetic (PK) analysis of celecoxib. Area Under The Plasma Concentration Versus Time Curve From Time 0 To The Last Quantifiable Concentration (AUCt) is reported as hours•ng/mL (h•ng/mL). | Baseline, up to 336 hours post-dose | 
| Area Under The Plasma Concentration Versus Time Curve From Time 0 To Infinity (AUCinf) Of Celecoxib With And Without The Coadministration Of ALXN1840 | Blood samples were collected for pharmacokinetic (PK) analysis of celecoxib. Area Under The Plasma Concentration Versus Time Curve From Time 0 To Infinity (AUCinf) is reported as h•ng/mL. | Baseline, up to 336 hours post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax Of Molybdenum With Coadministration Of Celecoxib | Blood samples were collected for PK analysis of total molybdenum (as a measure of ALXN1840) and plasma ultrafiltrate (PUF) molybdenum. Cmax is reported as ng/mL. | Baseline, up to 336 hours post-dose | 
| AUCt Of Molybdenum With Coadministration Of Celecoxib | Blood samples were collected for PK analysis of total molybdenum (as a measure of ALXN1840) and PUF molybdenum. AUCt is reported as h•ng/mL. | Baseline, up to 336 hours post-dose | 
| AUCinf Of Molybdenum With Coadministration Of Celecoxib | Blood samples were collected for PK analysis of total molybdenum (as a measure of ALXN1840) and PUF molybdenum. AUCinf is reported as h•ng/mL. | Baseline, up to 336 hours post-dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cytochrome P450, Healthy, ALXN1840, Celecoxib, CYP2C9