Evidence map›Paper›PMID 35384529›Full record

Trial reportThe AAPS journal2022

An Investigation of Instability in Dried Blood Spot Samples for Pharmacokinetic Sampling in Phase 3 Trials of Verubecestat.

Melanie Anderson, Marissa F Dockendorf, Ian McIntosh, Iris Xie, Sheila Breidinger, Dongfang Meng, Sumei Ren, Wendy Zhong, Li Zhang, Brad Roadcap and 3 more

2 registry-linked trialsAbstract readClinical Trial, Phase III
PubMed Publisher
In one paragraph

Trial report in The AAPS journal, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to 2 registered trials, which are not on this map. Cited by 2 papers.

0numbers the graph read from it
0cells of the map it votes in
2citing papers in PubMed
0.3field-weighted citation impact, top 47% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

NCT01739348 phase2 / phase3terminatednot on this map

A Randomized, Placebo Controlled, Parallel-Group, Double Blind Efficacy and Safety Trial of MK-8931 With a Long Term Double-Blind Extension in Subjects With Mild to Moderate Alzheimer's Disease (Protocol No. MK-8931-017-10)(Also Known as SCH 900931, P07738)

TypeinterventionalSponsorMerck Sharp & Dohme LLCRan2012 to 2017Enrolled2,211ConditionsAlzheimer's DiseaseArmsVerubecestat (Part I and Part II), Placebo (Part I), Verubecestat (Part II)
NCT01953601 phase3terminatednot on this map

A Phase III, Randomized, Placebo-Controlled, Parallel-Group, Double-Blind Clinical Trial to Study the Efficacy and Safety of MK-8931 (SCH 900931) in Subjects With Amnestic Mild Cognitive Impairment Due to Alzheimer's Disease (Prodromal AD)

TypeinterventionalSponsorMerck Sharp & Dohme LLCRan2013 to 2018Enrolled1,454ConditionsAmnestic Mild Cognitive Impairment, Alzheimer's Disease, Prodromal Alzheimer's DiseaseArmsVerubecestat 12 mg (Parts 1 and 2), Verubecestat 40 mg (Parts 1 and 2), Placebo (Part 1)
3 · Its place in the literature

Who cites it

2 citing papers in PubMed, 4 citations in OpenAlex.

  1. Review
  2. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

13 authors at 1 institution in 1 country.

Melanie AndersonPharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Inc., Kenilworth, New Jersey, USA. melanie_anderson@merck.com.
Marissa F DockendorfPharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Inc., Kenilworth, New Jersey, USA.
Ian McIntoshPharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Inc., Kenilworth, New Jersey, USA.
Iris XiePharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Inc., Kenilworth, New Jersey, USA.
Sheila BreidingerPharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Inc., Kenilworth, New Jersey, USA.
Dongfang MengProcess Chemistry, Merck & Co., Inc., Kenilworth, New Jersey, USA.
Sumei RenSM PR&D, Merck & Co., Inc., Kenilworth, New Jersey, USA.
Wendy ZhongAnalytical Research & Development, Merck & Co., Inc., Kenilworth, New Jersey, USA.
Li ZhangAnalytical Research & Development, Merck & Co., Inc., Kenilworth, New Jersey, USA.
Brad RoadcapPharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Inc., Kenilworth, New Jersey, USA.
Kevin P BatemanPharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Inc., Kenilworth, New Jersey, USA.
Julie StonePharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Inc., Kenilworth, New Jersey, USA.
Eric WoolfPharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Inc., Kenilworth, New Jersey, USA.
Merck & Co., Inc., Rahway, NJ, USA (United States) · US

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

In-clinic dried blood spot (DBS) pharmacokinetic (PK) sampling was incorporated into two phase 3 studies of verubecestat for Alzheimer's disease (EPOCH [NCT01739348] and APECS [NCT01953601]), as a potential alternative to plasma PK sampling for improved logistical feasibility and decreased blood volume burden. However, an interim PK analysis revealed verubecestat concentrations in DBS samples declined with time to assay in both trials. An investigation revealed wide variation in implementation practices for DBS sample handling procedures resulting in insufficient desiccation which caused verubecestat instability. High-resolution mass spectrometry evaluations of stressed and aged verubecestat DBS samples revealed the presence of two hydrolysis degradants. To minimize instability, new DBS handling procedures were implemented that provided additional desiccant and minimized the time to analysis. Both verubecestat hydrolysis products were previously discovered and synthesized during active pharmaceutical ingredient stability characterization. A liquid chromatography-mass spectrometry assay to quantitate the dominant verubecestat degradant in DBS samples was developed and validated. The application of this method to stressed and aged verubecestat DBS samples confirmed that degradant concentrations accounted for the observed decreases in the verubecestat concentration. Furthermore, after increasing desiccant amounts, degradant concentrations accounted for approximately 7% of the verubecestat concentration in DBS clinical samples, indicating that issues with sample handling were minimized with new storage and shipping conditions. This case study illustrates the challenges with employing new sampling techniques in large, global trials, and the importance of anticipating and mitigating implementation risks.

Indexed as

Dried Blood Spot TestingTandem Mass SpectrometryCyclic S-OxidesHumansHygroscopic AgentsSpecimen HandlingThiadiazinesCyclic S-OxidesHygroscopic AgentsThiadiazinesverubecestatDried blood spotsPharmacokinetic samplingStabilityVerubecestat

Identifiers

PMID35384529
OpenAlexW4223470408

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.