Evidence map›Paper›PMID 33891333›Full record

Trial reportBritish journal of clinical pharmacology2021

Safety, pharmacokinetics and pharmacodynamics of HTL0009936, a selective muscarinic M

Charlotte Bakker, Samantha Prins, Jan Liptrot, Ellen P Hart, Erica S Klaassen, Giles A Brown, Alastair Brown, Miles Congreve, Malcolm Weir, Fiona H Marshall and 5 more

Open access · hybridAbstract readRandomized Controlled Trial
In one paragraph

Trial report in British journal of clinical pharmacology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.

0numbers the graph read from it
0cells of the map it votes in
3citing papers in PubMed
0.2field-weighted citation impact, top 52% 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.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

3 citing papers in PubMed, 7 citations in OpenAlex.

  1. Trial
  2. Review
  3. Review
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

15 authors at 7 institutions in 4 countries.

Charlotte BakkerCentre for Human Drug Research, Leiden, The Netherlands.ORCID 0000-0001-9822-2354
Samantha PrinsCentre for Human Drug Research, Leiden, The Netherlands.
Jan LiptrotSosei Heptares, Cambridge, UK.
Ellen P HartCentre for Human Drug Research, Leiden, The Netherlands.
Erica S KlaassenCentre for Human Drug Research, Leiden, The Netherlands.
Giles A BrownSosei Heptares, Cambridge, UK.
Alastair BrownSosei Heptares, Cambridge, UK.
Miles CongreveSosei Heptares, Cambridge, UK.
Malcolm WeirSosei Heptares, Cambridge, UK.
Fiona H MarshallSosei Heptares, Cambridge, UK.
Jasper StevensCentre for Human Drug Research, Leiden, The Netherlands.ORCID 0000-0003-1601-9008
David M CrossCross Pharma Consulting Ltd, Cambridge, UK.
Tim TaskerSosei Heptares, Cambridge, UK.
Pradeep J NathanSosei Heptares, Cambridge, UK.
Geert Jan GroeneveldCentre for Human Drug Research, Leiden, The Netherlands.
Heptares Therapeutics (United Kingdom) · GBLeiden University Medical Center · NLCentre for Human Drug Research · NLBridge Pharma (United States) · USMerck & Co., Inc., Rahway, NJ, USA (United States) · USUniversity Medical Center Groningen · NLUniversity of Cambridge · GB

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

aimsHTL0009936 is a selective M

methodsPart A was a four-treatment open label sequential study in healthy elderly investigating 10-83 mg HTL0009936 (IV) and a 24 mg HTL0009936 single oral dose. Part B was a five-treatment randomized, double-blind, placebo and physostigmine controlled cross-over study with IV HTL0009936 in elderly subjects with BACF. Pharmacodynamic assessments were performed using neurocognitive and electrophysiological tests.

resultsPharmacokinetics of HTL0009936 showed dose-proportional increases in exposure with a mean half-life of 2.4 hours. HTL0009936 was well-tolerated with transient dose-related adverse events (AEs). Small increases in mean systolic blood pressure of 7.12 mmHg (95% CI [3.99-10.24]) and in diastolic of 5.32 mmHg (95% CI [3.18-7.47]) were noted at the highest dose in part B. Overall, there was suggestive, but no definitive, positive or negative pharmacodynamic effects. Statistically significant effects were observed on P300 with HTL0009936 and adaptive tracking with physostigmine.

conclusionsHTL0009936 showed well-characterized pharmacokinetics and single doses were safe and generally well-tolerated in healthy elderly subjects. Due to physostigmine tolerability issues and subject burden, the study design was changed and some pharmacodynamic assessments (neurocognitive) were performed at suboptimal drug exposures. Therefore no clear conclusions can be made on pharmacodynamic effects of HTL0009936, although an effect on P300 is suggestive of central target engagement.

Indexed as

Cholinergic AgentsReceptors, CholinergicAgedArea Under CurveCross-Over StudiesDose-Response Relationship, DrugDouble-Blind MethodHumansCholinergic AgentsReceptors, CholinergicAlzheimer's diseasecholinergic systemelderlyM1 receptormuscarinic receptorspharmacokineticssafety

Identifiers

PMID33891333
PMCPMC8596821
OpenAlexW3154892305

What OpenQuestion holds

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LicenceCC BY-NC-ND
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Registered trials

None linked

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.