Evidence map›Paper›PMID 26370183›Full record

ReviewJournal of neurotrauma2017

Suboptimal Dosing Parameters as Possible Factors in the Negative Phase III Clinical Trials of Progesterone for Traumatic Brain Injury.

Randy B Howard, Iqbal Sayeed, Donald G Stein

Open access · hybridAbstract readReview
PubMed Full text at PMC Publisher
In one paragraph

Review in Journal of neurotrauma, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers, 3 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
30citing papers in PubMed, 3 pooled it
14.0field-weighted citation impact, top 1% 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

30 citing papers in PubMed, 3 syntheses or guidelines pooled it, 70 citations in OpenAlex.

  1. Pooled it
  2. Pooled it
  3. Pooled it
  4. Review
  5. Review
  6. Improvement in edema and cognitive recovery after moderate traumatic brain injury with the neurosteroid prodrug NTS-104.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2024
    Article
  7. Article
  8. Review
  9. Review
  10. Article
  11. Article
  12. Article
  13. Review
  14. Article
  15. Article
  16. Non-clinical studies of progesterone.Climacteric : the journal of the International Menopause Society · 2018
    Review
  17. Neuroprotective strategies for retinal disease.Progress in retinal and eye research · 2018
    Review
  18. Review
  19. Neurobehavioral testing in subarachnoid hemorrhage: A review of methods and current findings in rodents.Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism · 2017
    Review
  20. 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

3 authors at 1 institution in 1 country.

Randy B Howard1 Pharmacology Consultant, Drug Discovery and Development, Emory University , Atlanta, Georgia .
Iqbal Sayeed2 Department of Emergency Medicine, Emory University , Atlanta, Georgia .
Donald G Stein2 Department of Emergency Medicine, Emory University , Atlanta, Georgia .
Emory University · US

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

To date, outcomes for all Phase III clinical trials for traumatic brain injury (TBI) have been negative. The recent disappointing results of the Progesterone for the Treatment of Traumatic Brain Injury (ProTECT) and Study of a Neuroprotective Agent, Progesterone, in Severe Traumatic Brain Injury (SyNAPSe) Phase III trials for progesterone in TBI have triggered considerable speculation about the reasons for the negative outcomes of these two studies in particular and for those of all previous Phase III TBI clinical trials in general. Among the factors proposed to explain the ProTECT III and SyNAPSe results, the investigators themselves and others have cited: 1) the pathophysiological complexity of TBI itself; 2) issues with the quality and clinical relevance of the preclinical animal models; 3) insufficiently sensitive clinical endpoints; and 4) inappropriate clinical trial designs and strategies. This paper highlights three critical trial design factors that may have contributed substantially to the negative outcomes: 1) suboptimal doses and treatment durations in the Phase II studies; 2) the strategic decision not to perform Phase IIB studies to optimize these variables before initiating Phase III; and 3) the lack of incorporation of the preclinical and Chinese Phase II results, as well as allometric scaling principles, into the Phase III designs. Given these circumstances and the exceptional pleiotropic potential of progesterone as a TBI (and stroke) therapeutic, we are advocating a return to Phase IIB testing. We advocate the incorporation of dose and schedule optimization focused on lower doses and a longer duration of treatment, combined with the addressing of other potential trial design problems raised by the authors in the recently published trial results.

Indexed as

AnimalsBrain Injuries, TraumaticClinical Trials, Phase II as TopicClinical Trials, Phase III as TopicDose-Response Relationship, DrugGlasgow Coma ScaleHumansNeuroprotective AgentsProgesteroneProgestinsNeuroprotective AgentsProgesteroneProgestinsallometric scalingPhase III trialsprogesteronesuboptimal dosing

Identifiers

PMID26370183
PMCPMC5455214
OpenAlexW1926546077

What OpenQuestion holds

Textmetadata
LicenceCC BY-NC
Read underepoch 390

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.